Early progression after bendamustine-rituximab is associated with high risk of transformation in advanced stage follicular lymphoma.
Freeman Ciara L,Kridel Robert,Moccia Alden A,Savage Kerry J,Villa Diego R,Scott David W,Gerrie Alina S,Ferguson David,Cafferty Fergus,Slack Graham W,Farinha Pedro,Skinnider Brian,Connors Joseph M,Sehn Laurie H
Despite widespread use of bendamustine and rituximab (BR) as frontline therapy for advanced-stage follicular lymphoma (FL), little is known about the risk of early progression or incidence of histological transformation. We performed a retrospective analysis of a population-based cohort of 296 patients with advanced-stage FL treated with frontline BR and maintenance rituximab. As previously demonstrated, outcomes with this regimen are excellent, with 2-year event-free survival estimated at 85% (95% confidence interval [95% CI], 80-89) and 2-year overall survival 92% (95% CI, 88-95). Progression of disease within 24 months (POD24) occurred in 13% of patients and was associated with a significantly inferior outcome with 2-year overall survival of 38% (95% CI, 20-55). The only significant risk factor for POD24 at baseline was elevated lactate dehydrogenase ( < .001). Importantly, the majority of POD24 patients (76%) had transformed disease. Compared with a historical cohort treated with rituximab, cyclophosphamide, vincristine, and prednisone, event-free survival has improved and the risk of POD24 has decreased, but a higher proportion of patients with POD24 harbor transformation. The overall incidence of transformation appears unchanged. The presence of occult or early transformation is the main driver of POD24 in FL patients treated with frontline BR. Identification of biomarkers and improved management strategies for transformation will be crucial to improving outcomes.
Comparison of the Long-Term Remission of Rituximab and Conventional Treatment for Acquired Thrombotic Thrombocytopenic Purpura: A Systematic Review and Meta-Analysis.
Owattanapanich Weerapat,Wongprasert Chompunut,Rotchanapanya Wannaphorn,Owattanapanich Natthida,Ruchutrakool Theera
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis
The current systematic review and meta-analysis aimed to summarize the results of all available studies to compare the efficacies of rituximab and conventional treatment for acquired thrombotic thrombocytopenic purpura (TTP). Three investigators independently searched studies in the MEDLINE and EMBASE databases published before December 11, 2018. To be included in the meta-analysis, studies needed to be randomized-controlled or cohort studies comparing the efficacies of rituximab and conventional therapy for TTP treatment. The effect estimates and 95% confidence intervals (CIs) from each study were collected, and Mantel-Haenszel methods were used to pool the data. A total of 570 patients from 9 eligible studies were included in the meta-analysis (280 patients in the rituximab arm and 290 in the conventional treatment arm). Patients receiving rituximab in an acute phase to induce disease remission had a significantly lower relapse rate than those given conventional treatment (odds ratio [OR]: 0.40, 95% CI: 0.19-0.85, P = .02, I = 43%). Similarly, the relapse rate in the rituximab group for preemptive therapy to prevent clinical relapse was also significantly lower than in the control group (OR: 0.09, 95% CI: 0.04-0.24, P < .00001, I = 11%). Furthermore, the conventional treatment group had a significantly higher mortality rate than the rituximab group during the follow-up (OR: 0.41, 95% CI: 0.18-0.91, P = .03, I = 0%). Rituximab offered high efficacy for the prevention of relapses and lower mortality rate in cases of acquired TTP.
Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma.
Hill Brian T,Nastoupil Loretta,Winter Allison M,Becnel Melody R,Cerhan James R,Habermann Thomas M,Link Brian K,Maurer Matthew J,Fakhri Bita,Reddy Prathima,Smith Stephen D,Mukhija Dhruvika,Jagadeesh Deepa,Desai Amrita,Alderuccio Juan Pablo,Lossos Izidore S,Mehra Pooja,Portell Craig A,Goldman Max L,Calzada Oscar,Cohen Jonathon B,Hussain Mohammad J,Ghosh Nilanjan,Caimi Paolo,Tiutan Timothy,Martin Peter,Kodali Abhigna,Evens Andrew M,Kahl Brad S
British journal of haematology
Bendamustine (B) with rituximab (R) is a standard frontline treatment for medically fit follicular lymphoma (FL) patients. The safety and efficacy of maintenance rituximab (MR) after BR induction has not been formally compared to observation for FL, resulting in disparate practice patterns. Prospective trials have shown benefit of MR after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), yet recent data from the GALLIUM study comparing outcomes of patients treated with chemotherapy with R or obinutuzumab (G) showed higher than anticipated fatal adverse events with BR/BG. In order to assess the efficacy and tolerability of MR after BR, we retrospectively collected data on 640 newly diagnosed patients treated with FL. We found that patients who achieved partial remission (PR) after ≥4 cycles of BR had improved duration of response (DOR) with MR vs. no maintenance, whereas those in complete remission did not. These findings were confirmed in a validation cohort. In the entire study population, the known fatal adverse event rate after BR was 2·5% and did not significantly differ in those receiving MR versus no maintenance. [Correction added on 14 January 2019, after online publication: The preceding sentence has been corrected in this current version.] Within the limitations inherent to retrospective analysis, these data suggest that FL patients with a PR to BR experience prolongation of remission with MR with an acceptable safety profile.
Long-term tolerability, safety and efficacy of rituximab in neuromyelitis optica spectrum disorder: a prospective study.
Shaygannejad V,Fayyazi E,Badihian S,Mirmosayyeb O,Manouchehri N,Ashtari F,Asgari N
Journal of neurology
BACKGROUND:Neuromyelitis optica spectrum disorder (NMOSD) is a B-cell-mediated disease with autoimmunity towards the astrocyte water channel aquaporin-4 (AQP-4) in the central nervous system. OBJECTIVE:To assess the long-term safety and efficacy in NMOSD patients receiving maintenance therapy with B-cell-depleting agent rituximab for more than 2 years. METHOD:NMOSD patients were included prospectively from 2014 to 2018 and received continuous cycles of rituximab infusions biannually. Incidence of adverse events (AE), serious AEs (SAE), and infusion-related AEs were evaluated through monthly phone calls and neurological examination every 4 months. RESULTS:A total of 44 NMOSD patients were included, of those 30 were treatment naive (68%). The mean age was 37.2 years with 79.5% females. With overall observation period of 31.6 ± 7.3 months (24-48 months), tolerability was assessed as satisfactory in most cases. We observed infusion reactions (mostly mild) in 31.8% of patients and 31.8% never experienced any AEs after a mean 5.1 cycles of rituximab therapy. Rituximab was also beneficial in terms of improvement in relapse rate (from 0.26 ± 0.54 to 0, P = 0.003) and Expanded Disability Status Scale (from 4.1 ± 1.8 to 3.1 ± 1.8, P < 0.001). Stratification according to AQP4-IgG serostatus showed no difference between groups. CONCLUSION:Rituximab treatment is well tolerated, safe, and efficacious with a minor risk of mild infusion reactions for NMOSD patients.
Treatment with alemtuzumab or rituximab after fingolimod withdrawal in relapsing-remitting multiple sclerosis is effective and safe.
Alcalá Carmen,Gascón F,Pérez-Miralles Francisco,Domínguez J A,Gil-Perotín S,Casanova B
Journal of neurology
BACKGROUND:It has been described that treating relapsing-remitting multiple sclerosis (RRMS) patients with alemtuzumab following fingolimod could be less effective due to the different dynamics of lymphocyte repopulation. Effectiveness and safety of alemtuzumab compared to rituximab after fingolimod withdrawal were analyzed. PATIENTS AND METHODS:A follow-up of a cohort of RRMS patients treated with alemtuzumab or rituximab after fingolimod withdrawal was accomplished. Effectiveness, measured by the percentage of patients with no evidence of disease activity (NEDA), and the presence of side effects (SE) were registered. RESULTS:Fifty-five patients, 28 with alemtuzumab and 27 with rituximab, were analyzed. No differences in the washout period or in the baseline lymphocytes counts were observed. After a mean follow-up period of 28.8 months, the annualized relapsing rate was significantly reduced in the alemtuzumab group from 1.29 to 0.004 (p < 0.001) and in the rituximab group from 1.24 to 0.02 (p < 0.001), without differences. A significant reduction of the median EDSS from 2.8 to 2.0 in the alemtuzumab group and from 3.5 to 2.5 (p < 0.01) in the rituximab group was observed, without differences. Eighty-two per cent (n = 28) of patients in alemtuzumab group and 69.2% (n = 26) in rituximab group achieved NEDA criteria, without differences (p = 0.3). Symptoms related to the infusion were the most frequent SE in both groups. No serious SE were registered. CONCLUSION:Treating RRMS patients with alemtuzumab or rituximab after fingolimod withdrawal is effective and safe, without significant differences between both groups in our series.
Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.
Poeschel Viola,Held Gerhard,Ziepert Marita,Witzens-Harig Mathias,Holte Harald,Thurner Lorenz,Borchmann Peter,Viardot Andreas,Soekler Martin,Keller Ulrich,Schmidt Christian,Truemper Lorenz,Mahlberg Rolf,Marks Reinhard,Hoeffkes Heinz-Gert,Metzner Bernd,Dierlamm Judith,Frickhofen Norbert,Haenel Mathias,Neubauer Andreas,Kneba Michael,Merli Francesco,Tucci Alessandra,de Nully Brown Peter,Federico Massimo,Lengfelder Eva,di Rocco Alice,Trappe Ralf,Rosenwald Andreas,Berdel Christian,Maisenhoelder Martin,Shpilberg Ofer,Amam Josif,Christofyllakis Konstantinos,Hartmann Frank,Murawski Niels,Stilgenbauer Stephan,Nickelsen Maike,Wulf Gerald,Glass Bertram,Schmitz Norbert,Altmann Bettina,Loeffler Markus,Pfreundschuh Michael, ,
Lancet (London, England)
BACKGROUND:Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis. METHODS:This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m), doxorubicin (50 mg/m), and vincristine (1·4 mg/m, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421. FINDINGS:Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy. INTERPRETATION:In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population. FUNDING:Deutsche Krebshilfe.
Proposed rituximab biosimilar BCD-020 versus reference rituximab for treatment of patients with indolent non-Hodgkin lymphomas: An international multicenter randomized trial.
Poddubnaya Irina V,Alekseev Sergey M,Kaplanov Kamil D,Lukavetskyy Les M,Rekhtman Grigoriy B,Dolai Tuphan K,Attili V Satya Suresh,Bermúdez Carlos D,Isaev Aleksandr A,Chernyaeva Ekaterina V,Ivanov Roman A
BCD-020 is a proposed rituximab biosimilar, which has shown high similarity to rituximab in quality and nonclinical studies in vitro and in vivo. International multicenter clinical trial was conducted to compare efficacy and safety of BCD-020 and reference rituximab in adult (older than 18 years) patients with indolent lymphomas (follicular lymphoma grade 1-2, splenic marginal zone lymphoma, and nodal marginal zone lymphoma). Pharmacokinetics, pharmacodynamics, and immunogenicity were also studied. Patients with no previous biologic treatment for lymphoma were randomly assigned 1:1 to receive BCD-020 or comparator 375 mg/m for 4 weeks. Primary study outcome was day 50 overall response rate defined as complete or partial remission. Equivalence range was -20% to 20% for 95% CI for overall response rates difference. Secondary outcomes included adverse events, pharmacokinetics, pharmacodynamics, and immunogenicity. One hundred seventy-four patients were enrolled, 89 in BCD-020 arm and 85 in comparator arm. The overall response rate was 44.71% in BCD-020 arm and 41.89% in comparator arm. Limits of 95% confidence interval (CI) for difference of overall response rates between arms were (-12.62%-18.24%) showing equivalent efficacy. Sixty-one (68.54%) and 59 (69.41%) patients had at least one adverse event in BCD-020 arm or comparator arm, respectively. No unexpected adverse reactions were reported. Antidrug antibodies with no neutralizing activity were detected in two patients in comparator arm on day 14 further declining below detection threshold. Rituximab concentrations had equivalent pattern after intravenous administration of both drugs. Both drugs caused depletion of B-cells without significant influence on other blood cell lineages. In this study, we showed equivalent efficacy of BCD-020 and reference rituximab when used in patients with CD20-positive indolent lymphomas. We also confirmed pharmacokinetic equivalence of BCD-020 and reference rituximab. Safety profile, pharmacodynamics, and immunogenicity of BCD-020 were also comparable with those of reference rituximab.
Ublituximab (TG-1101), a novel glycoengineered anti-CD20 antibody, in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukaemia: results of a phase 2 trial.
Sharman Jeff P,Farber Charles M,Mahadevan Daruka,Schreeder Marshall T,Brooks Heather D,Kolibaba Kathryn S,Fanning Suzanne,Klein Leonard,Greenwald Daniel R,Sportelli Peter,Miskin Hari P,Weiss Michael S,Burke John M
British journal of haematology
Ibrutinib is effective in patients with chronic lymphocytic leukaemia (CLL); however, treatment resistance remains a problem. Ublituximab is a novel, glycoengineered anti-CD20 monoclonal antibody with single-agent activity in relapsed CLL. We report the results of a phase 2 study evaluating combination therapy with ibrutinib and ublituximab in patients with relapsed or refractory CLL. Patients received ibrutinib 420 mg once daily. Ublituximab was administered on days 1, 8 and 15 of cycle 1 followed by day 1 of cycles 2-6. Response assessments were completed at cycles 3 and 6; patients then continued on ibrutinib monotherapy per standard of care. Forty-one of 45 enrolled patients were evaluable for efficacy. Safety was consistent with prior experience for each drug, with infusion reactions the most prevalent adverse event. Combination therapy resulted in an overall response rate (ORR) of 88% at 6 months. In the 20 patients with high-risk features (17p or 11q deletions or TP53 mutation) and evaluable for efficacy, the ORR was 95%, with three patients (15%) achieving negative minimal residual disease. Median time to response was 8 weeks. Ublituximab in combination with ibrutinib resulted in rapid and high response rates. The long-term clinical benefit of ublituximab will be defined by an ongoing phase 3 trial (NCT 02301156).
CD20 as a target for therapeutic type I and II monoclonal antibodies.
Beers Stephen A,Chan Claude H T,French Ruth R,Cragg Mark S,Glennie Martin J
Seminars in hematology
The last decade has seen the monoclonal antibody (mAb), rituximab, transform clinical management of many non-Hodgkin lymphomas and more recently provide new opportunities for controlling autoimmune conditions, such as rheumatoid arthritis. Although not yet fully determined, the explanation for this success appears to lie with the inherent properties of its target, CD20, which allow rituximab to recruit potent cytotoxic effectors with unusual efficiency. In this review we detail the properties of CD20 that make it such an effective therapeutic target and describe how different mAbs change the membrane distribution and internalization of CD20 and have distinct modes of cytotoxic activity.
Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies.
Tipton Thomas R W,Roghanian Ali,Oldham Robert J,Carter Matthew J,Cox Kerry L,Mockridge C Ian,French Ruth R,Dahal Lekh N,Duriez Patrick J,Hargreaves Philip G,Cragg Mark S,Beers Stephen A
Following the success of rituximab, 2 other anti-CD20 monoclonal antibodies (mAbs), ofatumumab and obinutuzumab, have entered clinical use. Ofatumumab has enhanced capacity for complement-dependent cytotoxicity, whereas obinutuzumab, a type II mAb, lacks the ability to redistribute into lipid rafts and is glycoengineered for augmented antibody-dependent cellular cytotoxicity (ADCC). We previously showed that type I mAbs such as rituximab have a propensity to undergo enhanced antigenic modulation compared with type II. Here we assessed the key effector mechanisms affected, comparing type I and II antibodies of various isotypes in ADCC and antibody-dependent cellular-phagocytosis (ADCP) assays. Rituximab and ofatumumab depleted both normal and leukemic human CD20-expressing B cells in the mouse less effectively than glycoengineered and wild-type forms of obinutuzumab, particularly when human immunoglobulin G1 (hIgG1) mAbs were compared. In contrast to mouse IgG2a, hIgG1 mAbs were ineffective in ADCC assays with murine natural killer cells as effectors, whereas ADCP was equivalent for mouse IgG2a and hIgG1. However, rituximab's ability to elicit both ADCC and ADCP was reduced by antigenic modulation, whereas type II antibodies remained unaffected. These data demonstrate that ADCP and ADCC are impaired by antigenic modulation and that ADCP is the main effector function employed in vivo.
Antitumor effects of an engineered and energized fusion protein consisting of an anti-CD20 scFv fragment and lidamycin.
Fang Hong,Miao Qingfang,Zhang Shenghua,Cheng Xin,Xiong Dongsheng,Zhen Yongsu
Science China. Life sciences
Antibody-based fusion proteins are the next generation of antibody therapies for cancer and other diseases. CD20 antigen, which is overexpressed on cell membranes in nearly 95% of cases of B-cell Non-Hodgkin's Lymphoma, is an attractive target for the therapy of B-lymphoid malignancies. Lidamycin (LDM) is a potent enediyne-containing antitumor antibiotic that now has entered phase II clinical trials. In this study, we prepared an engineered fusion protein, scFv-LDP, consisting of an anti-CD20 scFv fragment and the apoprotein LDP of LDM using DNA recombination. After purification and refolding, scFv-LDP was found to bind specifically to CD20-positive lymphoma cells using ELISA and indirect immunofluorescent cytochemical staining assays. The energized fusion protein scFv-LDP-AE was obtained using molecular reconstitution of the active chromophore AE of LDM and scFv-LDP. MTT assay revealed potent cytotoxicity of scFv-LDP-AE to CD20-positive Raji and Daudi cells, with IC(50) values of 1.21×10(-11) and 6.24×10(-11) mol L(-1), respectively. An in vivo subcutaneous xenograft model of CD20-positive B cell lymphoma in BALB/c (nu/nu) mice was also utilized. Drugs were given intravenously on day 14 and 21 after tumor transplantation. In terms of maximal tolerated doses, scFv-LDP-AE at 0.3 mg kg(-1) suppressed tumor growth by 79.3%, and LDM at 0.05 mg kg(-1) by 68.6% (P<0.05). Results suggested scFv-LDP-AE could be a potential candidate for tumor-targeting therapy.
The future of CD20 monoclonal antibody therapy in B-cell malignancies.
Czuczman Myron S,Gregory Stephanie A
Leukemia & lymphoma
Limitations of therapeutic options for chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) have necessitated the development of novel treatments/strategies. Rituximab (chimeric anti-CD20 monoclonal antibody [mAb]) considerably improved therapeutic outcomes for patients with B-cell malignancies, particularly when combined with chemotherapy; outcomes, however, are limited by rituximab resistance or reduced response upon re-treatment. Novel anti-CD20 mAbs are in development that may enhance mAb therapy. Ofatumumab (human anti-CD20 mAb) induces highly potent cell lysis, including in cells with low CD20 expression, and is the most clinically advanced new anti-CD20 mAb. Positive phase III interim data for ofatumumab in fludarabine-refractory CLL that is also refractory to alemtuzumab or less suitable for alemtuzumab due to bulky (>5 cm) lymphadenopathy has led to FDA approval of this agent in this population. Preclinical and early clinical assessment of other novel anti-CD20 mAbs include: ocrelizumab, veltuzumab, GA101, AME-133v, and PRO131921; data suggest potential for improved efficacy over rituximab that will require substantiation in large-scale clinical trials. New treatment strategies and novel anti-CD20 mAbs have the potential to enhance long-term outcomes for CLL and NHL.
Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study.
Sehn Laurie H,Goy Andre,Offner Fritz C,Martinelli Giovanni,Caballero M Dolores,Gadeberg Ole,Baetz Tara,Zelenetz Andrew D,Gaidano Gianluca,Fayad Luis E,Buckstein Rena,Friedberg Jonathan W,Crump Michael,Jaksic Branimir,Zinzani Pier Luigi,Padmanabhan Iyer Swaminathan,Sahin Deniz,Chai Akiko,Fingerle-Rowson Günter,Press Oliver W
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Obinutuzumab (GA101), a novel glycoengineered type II anti-CD20 monoclonal antibody, demonstrated responses in single-arm studies of patients with relapsed/refractory non-Hodgkin lymphoma. This is the first prospective, randomized study comparing safety and efficacy of obinutuzumab with rituximab in relapsed indolent lymphoma. The primary end point of this study was the overall response rate (ORR) in patients with follicular lymphoma after induction and safety in patients with indolent lymphoma. PATIENTS AND METHODS:A total of 175 patients with relapsed CD20(+) indolent lymphoma requiring therapy and with previous response to a rituximab-containing regimen were randomly assigned (1:1) to four once-per-week infusions of either obinutuzumab (1,000 mg) or rituximab (375 mg/m(2)). Patients without evidence of disease progression after induction therapy received obinutuzumab or rituximab maintenance therapy every 2 months for up to 2 years. RESULTS:Among patients with follicular lymphoma (n = 149), ORR seemed higher for obinutuzumab than rituximab (44.6% v 33.3%; P = .08). This observation was also demonstrated by a blinded independent review panel that measured a higher ORR for obinutuzumab (44.6% v 26.7%; P = .01). However, this difference did not translate into an improvement in progression-free survival. No new safety signals were observed for obinutuzumab, and the incidence of adverse events was balanced between arms, with the exception of infusion-related reactions and cough, which were higher in the obinutuzumab arm. CONCLUSION:Obinutuzumab demonstrated a higher ORR without appreciable differences in safety compared with rituximab. However, the clinical benefit of obinutuzumab in this setting remains unclear and should be evaluated within phase III trials.
Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20(+) rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia (pre-B-ALL): potential targeted therapy in patients with poor risk CD20(+) BL and pre-B-ALL.
Awasthi Aradhana,Ayello Janet,Van de Ven Carmella,Elmacken Mona,Sabulski Anthony,Barth Matthew J,Czuczman Myron S,Islam Humayun,Klein Christian,Cairo Mitchell S
British journal of haematology
Obinutuzumab is a novel glycoengineered Type-II CD20 monoclonal antibody. CD20 is expressed in approximately 100% of children and adolescents with Burkitt lymphoma (BL) and 40% with precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL). We evaluated the anti-tumour activity of obinutuzumab versus rituximab against rituximab-resistant (Raji 4RH) and -sensitive (Raji) BL and pre-B-ALL (U698-M) cells in vitro and in human BL or Pre-B-ALL xenografted mice. We demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35·6 ± 3·1% vs. 25·1 ± 2·0%, (P = 0·001), Raji4RH 19·7 ± 2·2% vs. 7·9 ± 1·5% (P = 0·001) and U-698-M 47·3 ± 4·9% vs. 23·2 ± 0·5% (P = 0·001), respectively. Obinutuzumab versus rituximab also induced a significant increase in antibody-dependent cellular cytotoxicity (ADCC) with K562-IL15-41BBL expanded NK cells against Raji 73·8 ± 8·1% vs. 56·81 ± 4·6% (P = 0·001), Raji-4RH 40·0 ± 1·6% vs. 0·5 ± 1·1% (P = 0·001) and U-698-M 70·0 ± 1·6% vs. 45·5 ± 0·1% (P = 0·001), respectively. Overall survival in tumour xenografted mice receiving 30 mg/kg of obinutuzumab was significantly increased when compared to those receiving 30 mg/kg of rituximab in BL; Raji (P = 0·05), Raji4RH (P = 0·02) and U698-M (P = 0·03), respectively. These preclinical data suggest obinutuzumab is significantly superior to rituximab in inducing cell death, ADCC and against rituximab-sensitive/-resistant BL and pre-B-ALL xenografted mice. Taken together, these preclinical results provide evidence to suggest that future investigation of obinutuzumab is warranted in patients with relapsed/refractory CD20(+) BL and/or pre-B-ALL.
Molecular mechanisms of the antitumor effects of anti-CD20 antibodies.
Winiarska Magdalena,Glodkowska-Mrowka Eliza,Bil Jacek,Golab Jakub
Frontiers in bioscience (Landmark edition)
Anti-CD20 monoclonal antibodies (mAbs) have become the mainstay in the treatment of non-Hodgkin's lymphomas and have shown significant activity in patients with B-cell chronic lymphocytic leukemia. Antitumor action of these antibodies results from triggering of indirect effector mechanisms of the immune system that include activation of complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), or phagocytosis. Moreover, some studies indicate direct influence of anti-CD20 mAbs on tumor cells that leads to induction of various types of cell death. Despite the wealth of data on the mechanisms of cytotoxicity that accumulated over the last two decades their relative contribution to the therapeutic outcome is still difficult to predict in individual patients. Elucidation of molecular mechanisms of anti-CD20 mAbs action is necessary to deliver their maximal activity in rationally designed combinations with other therapeutic approaches and to design next generation anti-CD20 mAb with improved ability to eliminate tumor cells.
New anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoid malignancies.
Robak Tadeusz,Robak Ewa
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy
Over the last few years, new generations of anti-CD20 monoclonal antibodies (mAbs) have been developed for potential benefits over the classical, first-generation mAb rituximab. Compared with rituximab, new mAbs have enhanced antitumor activity resulting from increased complement-dependent cytotoxicity (CDC) and/or antibody-dependent cellular cytotoxicity (ADCC) and increased Fc binding affinity for the low-affinity variants of the FcγRIIIa receptor (CD16) on immune effector cells. The second-generation mAbs, which include ofatumumab, veltuzumab, and ocrelizumab, are humanized or fully human to reduce immunogenicity, but with an unmodified Fc region. Ofatumumab is a fully human anti-CD20 IgG1 mAb in clinical development for hematological malignancies and autoimmune diseases. Ofatumumab specifically recognizes an epitope encompassing both the small and large extracellular loops of CD20 molecule, and is more effective than rituximab at CDC induction and killing target cells. Veltuzumab (IMMU-106, hA20) is a humanized anti-CD20 mAb with complementarity-determining regions similar to rituximab. This antibody has enhanced binding avidities and a stronger effect on CDC compared with rituximab. Ocrelizumab is a humanized mAb with the potential for enhanced efficacy in lymphoid malignancies compared with rituximab due to increased binding affinity for the low-affinity variants of the FcγRIIIa receptor. The third-generation mAbs are also humanized mAbs, but in addition they have an engineered Fc to increase their binding affinity for the FcγRIIIa receptor. The third-generation mAbs include AME-133v, PRO131921 and GA-101. AME-133v (LY2469298) is a type I, humanized IgG1 mAb with enhanced affinity for FcγRIIIa receptor and an enhanced ADCC activity compared with rituximab. PRO131921 is a humanized anti-CD20 mAb engineered to have improved binding to FcγRIIIa and better ADCC compared with rituximab. GA-101 (RO5072759) is a fully humanized, type II, IgG1 mAb derived from humanization of the parental B-Ly1 mouse antibody and subsequent glycoengineering using GlycoMab® technology. GA-101 was designed for enhanced ADCC and superior direct cell-killing properties, in comparison with currently available type I antibodies. TRU-015 is a small modular immunopharmaceutical (SMIP) derived from key domains of an anti-CD20 antibody. TRU-015 represents a novel biological compound that retains Fc-mediated effector functions and is smaller than mAbs. In this article we review data on new anti-CD20 mAbs that are potentially useful in the treatment of lymphoid malignancies.
Characterization of a novel humanized anti-CD20 antibody with potent anti-tumor activity against non-Hodgkin's lymphoma.
Zhang Haifeng,Song Liping,Ye Hongtu,Hu Lide,Liang Wenlu,Liu Datao
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
BACKGROUND:Rituximab, a mouse Fab and human Fc chimeric antibody, has been widely used to treat Non-Hodgkin's lymphoma (NHL). However, only 48% of patients respond to the treatment and complete response rate is below 10%. Also, immunogenicity was reported in 17-20% patients receiving the treatment, making it unsuitable for long term diseases such as autoimmune disorders. It has been a hot research field to "humanize" rituximab toward improved efficacy and reduced immunogenicity. METHODS:In this study, an advanced antibody humanization technology was applied to the sequence of the anti-CD20 antibody 2B8, its sequence of which was based on the original murine monoclonal antibody of rituximab in Roche. The complementarity-determining regions (CDRs) of the humanized antibodies were further optimized through computer-aided molecular dock. RESULTS:Five novel humanized anti-CD20 antibodies 1-5(1635, 1534, 3637, 1634 and 1536) were generated and their immunogenicity was significantly decreased when compared to rituximab. The novel humanized anti-CD20 antibodies 1-5 retained the binding activity of their murine counterpart, as demonstrated by the fluorescence-activated cell-sorting analysis (FACS). When compared to rituximab, the humanized antibodies still have the similar properties on both complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Furthermore, its anti-tumor efficacy in xenograft model is comparable to that of rituximab. CONCLUSION:The humanized anti-CD20 antibodies 1-5 have lower immunogenicity than rituximab. And at the same time, they still retain the anti-tumor effect both in vitro and vivo.
The future of anti-CD20 monoclonal antibodies: are we making progress?
Alduaij Waleed,Illidge Tim M
The anti-CD20 monoclonal antibody (mAb) rituximab has revolutionized the treatment of B-cell malignancies. This unprecedented success has not only substantially changed the mindset of the clinical community about the ability of mAb to improve outcomes but has catalyzed the interest in the pharmaceutical industry to develop the next generation of anti-CD20 mAbs. Since the introduction of rituximab 15 years ago, we have learned much about the potential mechanisms underlying the therapeutic efficacy of anti-CD20 mAbs. In parallel, many novel anti-CD20 mAbs have entered the clinic, each designed with modifications to structure aimed at further improving efficacy. On review of the newer generation of anti-CD20 mAbs entering clinical trials, it appears that the link between the novel mechanistic insights and the development of these next-generation anti-CD20 mAbs is unclear. As we move into an era of personalized medicine, it will become increasingly important for us to develop closer links between the emerging mechanistic insights and the clinical development, to further enhance the potency of anti-CD20 mAbs beyond that achieved with rituximab.
Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study.
Younes Anas,Thieblemont Catherine,Morschhauser Franck,Flinn Ian,Friedberg Jonathan W,Amorim Sandy,Hivert Benedicte,Westin Jason,Vermeulen Jessica,Bandyopadhyay Nibedita,de Vries Ronald,Balasubramanian Sriram,Hellemans Peter,Smit Johan W,Fourneau Nele,Oki Yasuhiro
The Lancet. Oncology
BACKGROUND:Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non-Hodgkin lymphoma. METHODS:In this phase 1b, open-label, non-randomised study, patients were recruited across six centres in the USA and France. Eligibility was age 18 years or older and treatment-naive histopathologically confirmed CD20-positive B-cell non-Hodgkin lymphoma. In the dose-escalation phase (part 1), patients with diffuse large B-cell lymphoma, mantle-cell lymphoma, or follicular lymphoma were enrolled. The primary objective was to determine a recommended phase 2 dose of ibrutinib with a standard R-CHOP regimen, by assessing safety in all patients who received treatment. Patients received ibrutinib 280 mg, 420 mg, or 560 mg per day in combination with a standard R-CHOP regimen every 21 days. Safety of the recommended phase 2 dose was then assessed in a dose-expansion population, which consisted of patients with newly diagnosed diffuse large B-cell lymphoma (part 2). Secondary objectives included assessments of the proportion of patients who had an overall response, pharmacokinetics, and pharmacodynamics. This trial is registered with ClinicalTrials.gov, number NCT01569750. FINDINGS:From June 22, 2012, to March 25, 2013, 33 patients were enrolled (part 1: 17; part 2: 16) and 32 received ibrutinib plus R-CHOP treatment (one patient in the part 2 cohort withdrew). The maximum tolerated dose was not reached and the recommended phase 2 dose for ibrutinib was 560 mg per day. The most common grade 3 or greater adverse events included neutropenia (73% [24 of 33 patients]), thrombocytopenia (21% [seven patients]), and febrile neutropenia and anaemia (18% each [six patients]). The most frequently reported serious adverse events were febrile neutropenia (18% [six patients]) and hypotension (6% [two patients]). 30 (94%) of 32 patients who received one or more doses of combination treatment achieved an overall response. All 18 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose had an overall response. For those subtyped and treated at the recommended phase 2 dose, five (71%) of seven patients with the germinal centre B-cell-like subtype and two (100%) patients with the non-germinal centre B-cell-like subtype had a complete response. R-CHOP did not affect pharmacokinetics of ibrutinib, and ibrutinib did not alter the pharmacokinetics of vincristine. Pharmacodynamic data showed Bruton's tyrosine kinase was fully occupied (>90% occupancy) at the recommended phase 2 dose. INTERPRETATION:Ibrutinib is well tolerated when added to R-CHOP, and could improve responses in patients with B-cell non-Hodgkin lymphoma, but our findings need confirmation in a phase 3 trial. FUNDING:Janssen.
Obinutuzumab: a novel anti-CD20 monoclonal antibody for previously untreated chronic lymphocytic leukemia.
The Annals of pharmacotherapy
OBJECTIVE:To review and summarize data on obinutuzumab, which was approved by the Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL). DATA SOURCES:A PubMed literature search (August 2002 to March 2014) was conducted using the terms obinutuzumab, GA101, anti-CD20 antibody, and CLL. Data were also obtained through the FDA briefing documents and American Society of Hematology abstracts. STUDY SELECTION AND DATA EXTRACTION:The literature search was limited to human studies published in English. Priority was placed on trials of obinutuzumab in previously untreated CLL. DATA SYNTHESIS:Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody, with a higher affinity for CD20 epitope, leading to superior cytotoxicity compared with rituximab. The FDA approval was based on a phase III, randomized trial of chlorambucil monotherapy (n = 118), chlorambucil plus obinutuzumab (n = 333), or rituximab (n =330) in previously untreated elderly CLL patients. Obinutuzumab was administered intravenously as 1000 mg on days 1, 8, and 15 of cycle 1 and day 1 for subsequent cycles. Median progression-free survival was 26.7 months in the chlorambucil plus obinutuzumab arm. The incidence of grade 3 or higher adverse events in the obinutuzumab plus chlorambucil arm was as follows: neutropenia (33%), infusion-related reactions (20%), thrombocytopenia (10%), and infections (7%). CONCLUSION:Obinutuzumab in combination with chlorambucil is a safe and effective new treatment option for previously untreated elderly CLL patients. It should become the new preferred therapy for these patients with significant comorbidities who are not candidates for fludarabine-based therapy.
Epitope characterization and crystal structure of GA101 provide insights into the molecular basis for type I/II distinction of CD20 antibodies.
Niederfellner Gerhard,Lammens Alfred,Mundigl Olaf,Georges Guy J,Schaefer Wolfgang,Schwaiger Manfred,Franke Andreas,Wiechmann Kornelius,Jenewein Stefan,Slootstra Jerry W,Timmerman Peter,Brännström Annika,Lindstrom Frida,Mössner Ekkehard,Umana Pablo,Hopfner Karl-Peter,Klein Christian
CD20 is a cell-surface marker of normal and malignant B cells. Rituximab, a monoclonal antibody targeting CD20, has improved the treatment of malignant lymphomas. Therapeutic CD20 antibodies are classified as either type I or II based on different mechanisms of killing malignant B cells. To reveal the molecular basis of this distinction, we fine-mapped the epitopes recognized by both types. We also determined the first X-ray structure of a type II antibody by crystallizing the obinutuzumab (GA101) Fab fragment alone and in complex with a CD20 cyclopeptide. Despite recognizing an overlapping epitope, GA101 binds CD20 in a completely different orientation than type I antibodies. Moreover, the elbow angle of GA101 is almost 30° wider than in type I antibodies, potentially resulting in different spatial arrangements of 2 CD20 molecules bound to a single GA101 or rituximab molecule. Using protein tomography, different CD20 complexes were found to be associated with the 2 antibodies, and confocal microscopy showed different membrane compartmentalization of these subpopulations of the cellular CD20 pool. Our findings offer a possible molecular explanation for the different cellular responses elicited by type I and II antibodies.
A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells.
Piccione Emily C,Juarez Silvia,Liu Jie,Tseng Serena,Ryan Christine E,Narayanan Cyndhavi,Wang Lijuan,Weiskopf Kipp,Majeti Ravindra
Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20. These characteristics facilitate selective binding of BsAbs to tumor cells, leading to phagocytosis. Treatment of human NHL-engrafted mice with BsAbs reduced lymphoma burden and extended survival while recapitulating the synergistic efficacy of anti-CD47 and anti-CD20 combination therapy. These findings serve as proof of principle for BsAb targeting of CD47 with tumor-associated antigens as a viable strategy to induce selective phagocytosis of tumor cells and recapitulate the synergy of combination antibody therapy. This approach may be broadly applied to cancer to add a CD47 blocking component to existing antibody therapies.
Comparative assessment of clinically utilized CD20-directed antibodies in chronic lymphocytic leukemia cells reveals divergent NK cell, monocyte, and macrophage properties.
Rafiq Sarwish,Butchar Jonathan P,Cheney Carolyn,Mo Xiaokui,Trotta Rossana,Caligiuri Michael,Jarjoura David,Tridandapani Susheela,Muthusamy Natarajan,Byrd John C
Journal of immunology (Baltimore, Md. : 1950)
CD20 is a widely validated, B cell-specific target for therapy in B cell malignancies. Rituximab is an anti-CD20 Ab that prolongs survival of chronic lymphocytic leukemia (CLL) patients when combined with chemotherapy. Ofatumumab and GA101 (obinutuzumab) are CD20-directed Abs currently being developed as alternative agents to rituximab in CLL based upon different properties of enhanced direct cell death, NK cell-mediated Ab-dependent cellular cytotoxicity, or complement-dependent cytotoxicity. Despite widespread study, ofatumumab and GA101 have not been compared with each other, nor studied for their interactions with monocytes and macrophages which are critical for the efficacy of anti-CD20 Abs in murine models. In CLL cells, we show that direct cell death and complement-dependent cytotoxicity are greatest with GA101 and ofatumumab, respectively. GA101 promotes enhanced NK cell activation and Ab-dependent cellular cytotoxicity at high Ab concentrations. Ofatumumab elicits superior Ab-dependent cellular phagocytosis with monocyte-derived macrophages. GA101 demonstrated reduced activation of monocytes with diminished pERK, TNF-α release, and FcγRIIa recruitment to lipid rafts. These data demonstrate that GA101 and ofatumumab are both superior to rituximab against CLL cells via different mechanisms of potential tumor elimination. These findings bear relevance to potential combination strategies with each of these anti-CD20 Abs in the treatment of CLL.
Combination therapy with the type II anti-CD20 antibody obinutuzumab.
Klein Christian,Bacac Marina,Umana Pablo,Fingerle-Rowson Günter
Expert opinion on investigational drugs
INTRODUCTION:Obinutuzumab is a novel humanized type II glycoengineered anti-CD20 antibody approved for first-line treatment of chronic lymphocytic leukemia (CLL) in combination with chlorambucil and for treatment of rituximab-refractory follicular lymphoma (FL). Areas covered: We describe current preclinical and clinical evidence supporting the combination of obinutuzumab with not only chemotherapy but also novel targeted therapies for B-cell hematologic malignancies, and its application in chemoimmunotherapy. We also provide an overview of the current clinical trial landscape investigating novel combination therapies based on obinutuzumab. Expert opinion: Within the next 10 years the treatment of B-cell malignancies with obinutuzumab is expected to increasingly move towards chemotherapy-free regimens. Novel combinations of obinutuzumab will be explored with targeted therapies, antibody-drug conjugates, and/or other immunotherapeutic agents, with the aim to achieve clinically meaningful improvements in efficacy and patient safety.
Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab.
Rougé Lionel,Chiang Nancy,Steffek Micah,Kugel Christine,Croll Tristan I,Tam Christine,Estevez Alberto,Arthur Christopher P,Koth Christopher M,Ciferri Claudio,Kraft Edward,Payandeh Jian,Nakamura Gerald,Koerber James T,Rohou Alexis
Science (New York, N.Y.)
Cluster of differentiation 20 (CD20) is a B cell membrane protein that is targeted by monoclonal antibodies for the treatment of malignancies and autoimmune disorders but whose structure and function are unknown. Rituximab (RTX) has been in clinical use for two decades, but how it activates complement to kill B cells remains poorly understood. We obtained a structure of CD20 in complex with RTX, revealing CD20 as a compact double-barrel dimer bound by two RTX antigen-binding fragments (Fabs), each of which engages a composite epitope and an extensive homotypic Fab:Fab interface. Our data suggest that RTX cross-links CD20 into circular assemblies and lead to a structural model for complement recruitment. Our results further highlight the potential relevance of homotypic Fab:Fab interactions in targeting oligomeric cell-surface markers.
A Review of Obinutuzumab (GA101), a Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies.
Tobinai Kensei,Klein Christian,Oya Naoko,Fingerle-Rowson Günter
Advances in therapy
Obinutuzumab (GA101) is a novel, type II, glycoengineered, humanized anti-CD20 monoclonal antibody that has been developed to address the need for new therapeutics with improved efficacy in patients with lymphocytic leukemia and lymphoma of B-cell origin. Obinutuzumab has a distinct mode of action relative to type I anti-CD20 antibodies, such as rituximab, working primarily by inducing direct cell death and antibody-dependent cell-mediated cytotoxicity. Obinutuzumab is under investigation in a wide-ranging program of clinical trials in patients with B-cell malignancies. Efficacy as monotherapy has been reported in patients with relapsed/refractory indolent and aggressive non-Hodgkin lymphoma (NHL) and in chronic lymphocytic leukemia (CLL) of B-cell origin. Improved outcomes have also been noted when obinutuzumab is added to chemotherapy in patients with B-cell NHL, and superiority over rituximab has been reported with combination therapy in patients with CLL. Ongoing research is focusing on developing options for chemotherapy-free treatment and on new combinations of obinutuzumab with novel targeted agents.
Improving CD20 antibody therapy: obinutuzumab in lymphoproliferative disorders.
Prica Anca,Crump Michael
Leukemia & lymphoma
Soon after the anti-CD20 monoclonal antibody rituximab began to change the management of indolent and aggressive B cell lymphomas, development of alternative antibodies - including chemoimmunoconjugates - was undertaken. Among humanized and fully human CD20 antibodies, obinutuzumab has emerged as one antibody that seems to have lived up to the promise of improved efficacy based on in vitro and preclinical experiments. The data available, thus, far establish obinutuzumab's preferred role as the anti-CD20 antibody of choice in chronic lymphocytic leukemia and untreated follicular lymphoma, as well as an important addition to the treatment of rituximab-refractory indolent lymphomas. Additional trials in aggressive lymphoma are required to define the place of this new antibody in the management of patients with curable lymphoma subtypes. There are greater toxicities associated with this treatment, including increased infusion-related reactions and cytopenias, but these are manageable with standard supportive care measures.
What is the status of novel anti-CD20 antibodies for chronic lymphocytic leukemia and are they set to leave rituximab in the shadows?
Chaudhry Maria,Cheson Bruce D
Expert review of hematology
Chronic lymphocytic leukemia/small lymphocytic lymphoma is the most prevalent form of adult leukemia in western countries. Chemotherapy has been the mainstay of treatment for the last several decades. The introduction of biological, targeted agents (e.g., monoclonal antibodies) has dramatically improved treatment options. The addition of rituximab to fludarabine and cyclophosphamide has improved patient outcomes, as compared to fludarabine and cyclophosphamide. Nevertheless, chronic lymphocytic leukemia remains incurable, leaving considerable room for improvement. One approach would be to enhance the activity of the CD20 antibody. The next-generation monoclonal antibody ofatumumab has not demonstrated superiority over rituximab, whereas obinutuzumab-chlorambucil is superior to rituximab-chlorambucil. Recent efforts to combine anti-CD20 antibodies with new targeted therapies offer the potential to move toward alternative non-chemotherapy-based treatment approaches.
Reassessment of Anti-CD20 Therapy in Lymphoid Malignancies: Impact, Limitations, and New Directions.
Reagan Patrick M,Friedberg Jonathan W
Oncology (Williston Park, N.Y.)
The addition of anti-CD20 monoclonal antibodies to the treatment of B-cell malignancies has dramatically affected the field as well as the lives of patients. Rituximab in particular has been combined safely with conventional chemotherapy and has resulted in improved overall survival in major histologic subtypes of B-cell lymphoma and chronic lymphocytic leukemia. It is incorporated into the standard initial treatment of nearly all of these diseases. Novel anti-CD20 antibodies are currently under development. Two of these agents, ofatumumab and obinutuzumab, have been approved for use in certain clinical settings. Research comparing these newer antibodies with rituximab is ongoing. As these newer antibodies are further studied and developed, improvements in response and progression-free survival need to be considered in the context of clinical benefit as well as toxicity, especially in indolent diseases. Research involving rituximab biosimilars is ongoing as well, and recent preliminary data demonstrate similar efficacy and tolerability when compared with rituximab. An additional focus of ongoing research is the use of extended schedules of anti-CD20 monoclonal antibodies, as the optimal duration of therapy remains ill-defined in many histologic subtypes. To maximize the use of these agents, well-validated clinical trial endpoints will need to be carefully considered.
Ublituximab for the treatment of CD20 positive B-cell malignancies.
Babiker Hani M,Glode Ashley E,Cooke Laurence S,Mahadevan Daruka
Expert opinion on investigational drugs
INTRODUCTION:Non-Hodgkin lymphoma (NHL) is the most common adult hematologic malignancy. Conventional methods of treatment are chemotherapy and radiation, which were associated with toxicities and lack of specificity. Potential cell surface targets for treatment of B-cell NHL (B-NHL) include CD19, CD20, and CD22 which are highly expressed on malignant B-cells. The development of monoclonal antibody (mAb) therapy directed against CD20 had the most clinical impact in the treatment of B-NHL. Early clinical trials with rituximab (RTX), the first chimeric mAb against CD20, showed efficacy and minimal toxicities. RTX was later approved as first line in combination with CHOP chemotherapy for Diffuse Large B-NHL (DLBCL). The emergence of resistance to RTX prompted the development of the next-generation of mAbs targeting CD20 (e.g. obinituzumab, ofatumumab), and includes ublituximab (Ub), with higher complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) against malignant B-cells. Areas covered: Herein, we discuss clinical trials of Ub, highlighting efficacy, tolerability and an expert opinion on drug development in B-NHL. A pubmed search was conducted to evaluate all Ub clinical trials. Expert opinion: Ub demonstrated efficacy in patients with high-risk CLL and B-NHL in both first line, subsequent lines, and in rituximab refractory patients.
Optimization of anti-CD20 humanized antibody hu8E4 by site-directed mutation based on epitope analysis.
Chen Yalin,Chen Lin,Lu Qiong,Meng Yanchun,Wang Chao,Wang Linfei,Wang Huajing,Yu Xiaojie,Zhang Yajun,Zhao Lei,Li Bohua,Guo Yajun
Biochemical and biophysical research communications
Despite the effectiveness of the anti-CD20 chimeric antibody (mAb), rituximab, in treating B-cell lymphomas, its efficacy remains variable and often modest. Hu8E4 is an anti-CD20 humanized antibody which exhibits markedly higher antitumor activity compared with rituximab. Previous studies have indicated that rituximab and almost all known anti-CD20 murine mAbs recognize the A170/P172 motif within the large extracellular loop of CD20. In this study, we demonstrated that hu8E4 also recognized the A170/P172 motif, suggesting that the epitopes recognized by rituximab and hu8E4 are very similar. Based on this, three single mutations (D57E, Y102K and Y102T) at the heavy chain variable region that can improve the affinity of rituximab were transferred to hu8E4. The results showed that D57E and Y102T but not Y102K successfully enhanced the binding of hu8E4 to CD20. Out of these hu8E4 mutants, hu8E4D57E exhibited the highest affinity. The in vitro and in vivo antitumor activity of hu8E4D57E was further investigated. Our data indicated that hu8E4D57E was as effective as hu8E4 in mediating CDC and inducing apoptosis in B-lymphoma cells, but it was more potent in ADCC than hu8E4. Importantly, hu8E4D57E was shown to be significantly more effective than Hu8E4 in prolonging the survival of SCID mice bearing disseminated B-lymphoma cells, suggesting that it might be a promising therapeutic agent for B-cell lymphomas. Moreover, this study also suggests that the mutations that can improve the affinity of rituximab may be transferred to other anti-CD20 murine mAbs to enhance their binding to CD20.
Anti-CD20 antibody treatment of non-Hodgkin lymphomas.
Clinical immunology (Orlando, Fla.)
The CD20 antigen characteristic for mature B-cell is also expressed on B-cell Non-Hodgkin lymphomas (NHL). It thus presents a possible target for immunotherapy. NHL respond readily to radio- and/or chemotherapy but this standard treatment bears a high risk of relapse. The specific monoclonal anti-CD20-antibody Rituximab, the first to be approved for clinical use, could be shown to improve response rates, response duration, and survival in NHL when combined with standard therapy. This review details the development, clinical application, and future perspectives of anti-CD20-antibody treatment of NHL, thereby proving the efficiency of immunotherapy via targeting of a tumor associated antigen.
Improving therapeutic activity of anti-CD20 antibody therapy through immunomodulation in lymphoid malignancies.
Lipowska-Bhalla Grazyna,Fagnano Ester,Illidge Timothy M,Cheadle Eleanor J
Leukemia & lymphoma
Nearly two decades ago rituximab heralded a new era in management of B cell malignancies significantly increasing response rates and survival. However, despite clear therapeutic advantage, significant numbers of patients become refractory to anti-CD20 mAb therapy, suggesting urgent improvements are required. It is now well recognized that the suppressive tumor microenvironment plays an important role in the outcome of anti-CD20 mAb therapy and that manipulation of this environment may improve the efficacy and produce long-term tumor control. The past few years have seen a surge of interest in immunomodulatory agents capable of overwriting immune suppressive networks into favorable clinical outcome. Currently, a number of such combinations with anti-CD20 mAb is under evaluation and some have produced encouraging outcomes in rituximab refractory disease. In this review, we give an outline of anti-CD20 mAbs and explore the combinations with immunomodulatory agents that enhance antitumor immunity through targeting stimulatory or inhibitory pathways and have proven potential to synergize with anti-CD20 mAb therapy. These agents, primarily mAbs, target CTLA-4, PD-1/PD-L1, and CD40.
CD20-Mimotope Peptide Active Immunotherapy in Systemic Lupus Erythematosus and a Reappraisal of Vaccination Strategies in Rheumatic Diseases.
Favoino Elvira,Prete Marcella,Marzullo Andrea,Millo Enrico,Shoenfeld Yehuda,Perosa Federico
Clinical reviews in allergy & immunology
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which any organs can be potential targets of autoimmune aggression. Although the pathogenic auto-antibodies have been well characterized, the role of B cells goes far beyond that of antibodies production, and B cell-targeted therapy may be an interesting therapeutic approach. The anti-CD20 monoclonal antibody rituximab has been successfully used to control the most severe form of SLE, and even if two controlled clinical trials failed to demonstrate its superiority compared to conventional immunosuppressants, off-label use of rituximab is still commonly adopted in clinical practice in SLE nephritis resistant to immunosuppressants. Different protocols have stipulated heterogeneous dosages but all of them included repeated injections of the drug, exposing the patient to the risk of adverse reactions and to tachyphylaxis (loss of the therapeutic effect). Stimulation of the host's immune system to develop a CD20 antigen-specific immune response by means of CD20-mimotope molecules may offer an approach that can overcome these drawbacks. This study provides a critical overview of vaccination therapy in rheumatic diseases and reports the design of a vaccination strategy in (New Zealand Black/New Zealand White) F1 SLE-prone mice using CD20-mimotope peptides. By week 47, this vaccine induces a B- cell depletion by 74 % (cell number, mean ± SD, 0.57 ± 0.38) as compared to week 29 (2.19 ± 0.55) (p = 0.005) and prolongs survival in peptide-treated mice (median, 46.71 weeks; 95 % CI, 39.78-53.64) as compared to the control group (median 39.85; 95 % CI, 37.41-42.30) (Kaplan-Meier p = 0.002), although no differences between the peptide group and control group were detected in terms of proteinuria and auto-antibodies titers. These data indicate the feasibility of this approach, and the mouse model described here may be useful to optimize vaccination protocol and to define the mechanism(s) underlying B- cell depletion.
CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies.
Safdari Yaghoub,Ahmadzadeh Vahideh,Farajnia Safar
Investigational new drugs
Expression of CD20 antigen by the most of transformed B cells is believed to be the driving force for targeting this molecule by using anti-CD20 monoclonal antibodies. While it is true that most lymphoma/leukemia patients can be cured, these regimens are limited by the emergence of treatment resistance. Based on these observations, development of anti-CD20 monoclonal antibodies and combination therapies have been recently proposed, in particular with the aim to optimize the cytotoxic activity. Here we outline a range of new experimental agents concerning the CD20 positive B-cell tumors which provide high benefit from conventional therapy.
Targeting CD20: teaching an old dog new tricks.
Sharman Jeff P
Hematology. American Society of Hematology. Education Program
Rituximab was the first monoclonal antibody used for the treatment of a malignancy. In the 22 years since initial approval, it has become a vital component of therapy for a multitude of B-cell malignancies. Within the last several years, however, there has been a robust development of novel agents targeting CD20, including second generation anti-CD20 antibodies, biosimilar antibodies, and subcutaneous formulations that have been approved. The era of passive immunotherapy is now yielding to therapeutic approaches that actively engage the immune system. Emerging approaches leverage immunomodulatory drugs or novel checkpoint inhibitors to enhance CD20 therapy. Recent data sets on bispecific CD3/CD20 antibodies demonstrate exciting early findings, and CD20-directed chimeric antigen receptor T-cell therapies are now entering clinical trials. Anti-CD20 therapies are a vital component of the treatment of B-cell malignancies, and there is a dynamic therapeutic environment with multiple new data sets reviewed here.
CD20 role in pathophysiology of Hodgkin's disease.
Santos Marcelo Antônio Oliveira,Lima Marinus de Moraes
Revista da Associacao Medica Brasileira (1992)
Hodgkin's lymphoma (HL) is a tumor comprising non-malignant and malignant B-cells. Classical HL expresses CD15+ and CD30+ antigens, and 20 to 40% of patients are CD20+. This antigen is a ligand free protein present in B lymphocyte cells and its function is not well known. Some studies suggest that expression of CD20 may play a major role in Hodgkin's disease pathophysiology and may affect the patients' treatment prognosis, as well as relapse and refractory response. In the past few years, development of monoclonal anti-CD20 antibodies changed drastically the treatment for non-Hodgkin lymphomas in which CD20 is expressed. HL treatment is essentially composed of radiotherapy and chemotherapy; however, monoclonal anti-CD20 antibodies applicability is not well delimitated due to lack of information about clinical outcomes with anti-CD20 monotherapy or combined drug therapy using a classic regimen, as well as about CD20 pathophysiology mechanisms in B-cells tumors. The objective of our review is to discuss CD20 function in Hodgkin's lymphoma development, its influence on disease evolution and outcomes, as well as its effects on therapeutics and patients' prognostic.
CD20-Mimotope Peptides: A Model to Define the Molecular Basis of Epitope Spreading.
Favoino Elvira,Prete Marcella,Catacchio Giacomo,Conteduca Giuseppina,Perosa Federico
International journal of molecular sciences
Antigen-mimicking peptide (mimotope)-based vaccines are one of the most promising forms of active-immunotherapy. The main drawback of this approach is that it induces antibodies that react poorly with the nominal antigen. The aim of this study was to investigate the molecular basis underlying the weak antibody response induced against the naïve protein after peptide vaccination. For this purpose, we analyzed the fine specificity of monoclonal antibodies (mAb) elicited with a 13-mer linear peptide, complementary to theantigen-combining site of the anti-CD20 mAb, Rituximab, in BALB/c mice. Anti-peptide mAb competed with Rituximab for peptide binding. Even so, they recognized a different antigenic motif from the one recognized by Rituximab. This explains their lack of reactivity with membrane (naïve) CD20. These data indicate that even on a short peptide the immunogenic and antigenic motifs may be different. These findings highlight an additional mechanism for epitope spreading and should be taken into account when designing peptides for vaccine purposes.
An IgG1-like bispecific antibody targeting CD52 and CD20 for the treatment of B-cell malignancies.
Qi Junpeng,Chen Shih-Shih,Chiorazzi Nicholas,Rader Christoph
Methods (San Diego, Calif.)
Bispecific antibodies (biAb) targeting two different antigens or two distinct epitopes on the same antigen have demonstrated broad therapeutic utility. CD52 and CD20 are co-expressed on the cell surface of malignant B cells in B-cell non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL) and increased expression of both antigens is detected on dividing or recently divided cells ("proliferative fraction") in CLL. The CD52-targeting monoclonal antibody (mAb) alemtuzumab (atz) not only depletes malignant B cells but also healthy CD52 B and T lymphocytes and monocytes, causing severe immunosuppression. Loss of CD20 can occur in CLL after treatment with rituximab (rtx) and other CD20-targeting mAbs. To broaden the benefit of atz and rtx, we engineered an IgG1-like biAb, atz × rtx scFv-Fc. The Fc fragment of the biAb facilitates purification by Protein A affinity chromatography and supports a longer circulatory half-life. While atz × rtx scFv-Fc retained both antigen binding specificities, it showed superior binding to CD52CD20 B cells compared to CD52CD20 T cells. Moreover, atz × rtx scFv-Fc mediated potent complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in vitro and exhibited B-cell depleting but T-cell sparing activities in vivo in a CLL patient-derived xenograft model. B-cell depletion was more pronounced for cells of the proliferative fraction.
Amplification of CD20 Cross-Linking in Rituximab-Resistant B-Lymphoma Cells Enhances Apoptosis Induction by Drug-Free Macromolecular Therapeutics.
Li Lian,Yang Jiyuan,Wang Jiawei,Kopeček Jindřich
Although the CD20-targeted monoclonal antibody rituximab (RTX) has revolutionized the therapeutic landscape for B-cell malignancy, relapsed and refractory disease due to RTX resistance continue to constitute major challenges, illustrating the need for better therapies. Here, we apply drug-free macromolecular therapeutics (DFMT) that amplifies CD20 cross-linking to enhance apoptosis in RTX-resistant cells. Bispecific engager (anti-CD20 Fab' conjugated with oligonucleotide1) pretargets CD20 and the deletion of Fc-region minimizes its premature endocytosis in resistant cells that rapidly internalize and consume CD20/RTX complexes. Second-step delivery of multivalent polymeric effector (linear copolymer conjugated with multiple copies of complementary oligonucleotide 2) simultaneously hybridizes multiple CD20-bound engagers and strengthens CD20 ligation. Moreover, the restoration of CD20 expression by the pretreatment of cells with a polymer-gemcitabine conjugate, a CD20 expression enhancer, unleashes the full potential of DFMT in the CD20-deficient resistant cells. Hence, amplification of CD20 cross-linking is achieved by (1) the enhancement of surface CD20 accessibility, (2) the increase in CD20 expression, and (3) multimeric CD20 binding, which ultimately translates into the amplified activation of a wide range of innate apoptotic responses. We demonstrated that the altered molecular signaling pathway that originally results in RTX resistance could be circumvented and compensated by other DFMT-augmented pathways. Of note, our preliminary data provide proof-of-concept that CD20 cross-linking amplification emerges as an important strategy for overcoming RTX resistance.
CD20 monoclonal antibodies for the treatment of multiple sclerosis: up-to-date.
Ancau Mihai,Berthele Achim,Hemmer Bernhard
Expert opinion on biological therapy
INTRODUCTION:Featuring demyelination and axonal degeneration, multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system representing a prominent cause of disability in young adults. The recently established therapeutic targeting of B cells in MS patients using CD20 monoclonal antibodies (CD20-mAbs) not only profoundly suppresses inflammatory disease activity but also materializes as the first treatment approach against disability accumulation in a subset of patients with primary progressive MS. AREAS COVERED:We will review current concepts regarding the immunopathology of B cells as well as results of clinical trials with CD20-mAbs in MS, from the murine-human chimeras rituximab and ublituximab to their increasingly humanized counterparts ocrelizumab and ofatumumab. We conducted a literature search using PubMed, clinicaltrials.gov, and clinicaltrialsregister.eu. We will focus on studies emphasizing the effectiveness of these mAbs in reducing MS disease activity and progression, long-term safety, optimal dosage and maintenance regimens. Lastly, we will turn to outstanding questions regarding anti-CD20 therapy in MS. EXPERT OPINION:CD20-mAbs could become first-line drugs in selected patients with highly active MS and already constitute an option for PPMS. Future studies could evaluate whether administration regimens currently in use can be optimized, while registry data could shed light on risk versus benefits on the long run, considering immunosenescence and a potentially increased risk of malignancies and infections in an aging population.
Therapeutic Antibodies: What Have We Learnt from Targeting CD20 and Where Are We Going?
Marshall Michael J E,Stopforth Richard J,Cragg Mark S
Frontiers in immunology
Therapeutic monoclonal antibodies (mAbs) have become one of the fastest growing classes of drugs in recent years and are approved for the treatment of a wide range of indications, from cancer to autoimmune disease. Perhaps the best studied target is the pan B-cell marker CD20. Indeed, the first mAb to receive approval by the Food and Drug Administration for use in cancer treatment was the CD20-targeting mAb rituximab (Rituxan). Since its approval for relapsed/refractory non-Hodgkin's lymphoma in 1997, rituximab has been licensed for use in the treatment of numerous other B-cell malignancies, as well as autoimmune conditions, including rheumatoid arthritis. Despite having a significant impact on the treatment of these patients, the exact mechanisms of action of rituximab remain incompletely understood. Nevertheless, numerous second- and third-generation anti-CD20 mAbs have since been developed using various strategies to enhance specific effector functions thought to be key for efficacy. A plethora of knowledge has been gained during the development and testing of these mAbs, and this knowledge can now be applied to the design of novel mAbs directed to targets beyond CD20. As we enter the "post-rituximab" era, this review will focus on the lessons learned thus far through investigation of anti-CD20 mAb. Also discussed are current and future developments relating to enhanced effector function, such as the ability to form multimers on the target cell surface. These strategies have potential applications not only in oncology but also in the improved treatment of autoimmune disorders and infectious diseases. Finally, potential approaches to overcoming mechanisms of resistance to anti-CD20 therapy are discussed, chiefly involving the combination of anti-CD20 mAbs with various other agents to resensitize patients to treatment.
Anti-CD20 Directed Therapy of B Cell Lymphomas: Are New Agents Really Better?
Freeman Ciara L,Sehn Laurie
Current oncology reports
PURPOSE OF REVIEW:Since its initial approval in 1997, rituximab has revolutionized the treatment of CD20-positive lymphoproliferative disorders. Now, over two decades later, second-generation molecules are emerging that may have key biological advantages compared to rituximab, as well as biosimilars that may be more cost-effective. Clinicians, health policy makers, and payers will now need to critically appraise the available evidence for these competitors and decide which anti-CD20 to use. RECENT FINDINGS:Evidence has emerged directly comparing rituximab IV to a subcutaneous preparation, and head-to-head comparisons of rituximab versus next-generation anti-CD20 monoclonal antibodies have also been published. Trials comparing rituximab with newly developed biosimilars have also allowed for registration of these agents. In this review, we will present an overview of anti-CD20 monoclonal antibody development, discuss the mechanistic and clinical evidence for rituximab, as well as the novel compounds, and provide commentary on the possible advantages and limitations of these agents.
Novel HDAC inhibitor Chidamide synergizes with Rituximab to inhibit diffuse large B-cell lymphoma tumour growth by upregulating CD20.
Guan Xu-Wen,Wang Hua-Qing,Ban Wei-Wei,Chang Zhi,Chen Hai-Zhu,Jia Li,Liu Feng-Ting
Cell death & disease
Loss of CD20 is a major obstacle for the retreatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL) with Rituximab-associated regimens. Histone deacetylation causes gene silencing and inhibits CD20 expression. Chidamide is a novel inhibitor for histone deacetylases (HDACs). We hypothesize that Chidamide could overcome Rituximab-mediated down-regulation of CD20 and facilitate Rituximab-induced killing. In this study, we determine the mechanism of synergy of Chidamide with Rituximab in DLBCL using in vitro and in vivo models. We found that the levels of CD20 protein surface expression on five DLBCL cell lines were significantly and positively correlated with the sensitivities of cells to Rituximab. Treatment with Rituximab significantly reduced CD20 surface expression at the protein levels. RNA sequencing showed that Chidamide significantly increased expression of more than 2000 transcriptomes in DLBCL cells, around 1000 transcriptomes belong to the cell membrane and cell periphery pathways, including MS4A1. Chidamide significantly increased CD20 surface expression in DLBCL cell lines. Combination with Chidamide significantly synergized Rituximab-induced cell death in vitro and significantly inhibited tumour growth in DLBCL-bearing xenograft mice. A patient with relapsed/refractory DLBCL achieved a complete response after three cycles combined treatment with Chidamide and Rituximab. In conclusion, our data demonstrate for the first time that inhibition of HDACs by Chidamide significantly enhanced Rituximab-induced tumour growth inhibition in vitro and in vivo. We propose that CD20 surface expression should be used clinically to evaluate treatment response in patients with DLBCL. Chidamide is a promising sensitizer for the retreatment of DLBCL with Rituximab.
Computer-aided Drug Designing for the Identification of High-Affinity Small Molecule Targeting CD20 for the Clinical Treatment of Chronic Lymphocytic Leukemia (CLL).
Sinha Kritika,Majhi Manisha,Thakur Garima,Patidar Khushboo,Sweta Jajoriya,Hussain Tajamul,Nayarisseri Anuraj,Singh Sanjeev Kumar
Current topics in medicinal chemistry
BACKGROUND:Chronic lymphocytic leukemia (CLL) is a B-lineage lymphoid malignancy of self-reactive cells that are focused to produce polyreactive natural autoantibodies. Its surface protein marker CD20 plays an important role in the humoral immune response targeting which has emerged as an attractive therapeutic option for the treatment of CLL. The present study explains the interaction of the CD20 with its established inhibitors and to discover the compound having high binding affinity against the target protein receptor. Technically, during the development of new compound through docking studies, best drug among all pre-exist drugs got filtered, hence in reference to docked best drug study moved ahead. METHODS:The 3D structure of CD20 was built using homology base fold recognition method using Smith waterman's Local alignment and standalone Delta Blast algorithms. 23 established inhibitors towards CD20 were selected in this present investigation. Among these inhibitors, etoposide (RMSD value -96.6481) showed high binding capacity with the receptor CD20 which was further subjected to virtual screening. The said screening presented 380 possible drugs having structural similarity to etoposide. RESULTS:The docking studies of the screened drugs separated the compound having PubChem CID: 11753896 (RMSD value -98.5416). Toxicity and interaction profile validated this compound for having a better affinity with the target protein. Conclusively, this research study says that according to ADMET profile and BOILED-Egg plot, the compound (PubChem CID: 11753896) obtained from Virtual Screen could be the best drug in future during the prevention of Chronic Lymphocytic Leukemia. CONCLUSION:The compound identified in the present investigation can be subjected further for in vitro and in vivo studies for ADMET properties and it could optimize a good profile in the field of pharmacy and bioavailable for suppressing cancer. The pharmacophore study revealed that the drug CID11753896 is a non-inhibitor of CYP450 microsomal enzymes and was found to be non-toxic, similar to the established compound CID36462. It has a lower LD50 value of 2.5423mol/kg as compared to the established compound whose LD50 value is 2.9588mol/kg. Also, the compound was found to be non-carcinogenic.
New insights in Type I and II CD20 antibody mechanisms-of-action with a panel of novel CD20 antibodies.
Meyer Saskia,Evers Mitchell,Jansen Johannes H M,Buijs Jos,Broek Blanca,Reitsma Stephanie E,Moerer Petra,Amini Mojtaba,Kretschmer Anna,Ten Broeke Toine,den Hartog Marcel T,Rijke Mark,Klein Christian,Valerius Thomas,Boross Peter,Leusen Jeanette H W
British journal of haematology
Based on their mechanisms-of-action, CD20 monoclonal antibodies (mAbs) are grouped into Type I [complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC)] and Type II [programmed cell death (PCD) and ADCC] mAbs. We generated 17 new hybridomas producing CD20 mAbs of different isotypes and determined unique heavy and light chain sequence pairs for 13 of them. We studied their epitope binding, binding kinetics and structural properties and investigated their predictive value for effector functions, i.e. PCD, CDC and ADCC. Peptide mapping and CD20 mutant screens revealed that 10 out of these 11 new mAbs have an overlapping epitope with the prototypic Type I mAb rituximab, albeit that distinct amino acids of the CD20 molecule contributed differently. Binding kinetics did not correlate with the striking differences in CDC activity among the mIgG2c mAbs. Interestingly, chimerization of mAb m1 resulted in a mAb displaying both Type I and II characteristics. PCD induction was lost upon introduction of a mutation in the framework of the heavy chain affecting the elbow angle, supporting that structural changes within this region can affect functional activities of CD20 mAbs. Together, these new CD20 mAbs provide further insights in the properties dictating the functional efficacy of CD20 mAbs.
The latest developments with anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia.
Evers Mitchell,Jak Margot,Leusen J H W
Expert opinion on biological therapy
INTRODUCTION:In more recent years, anti-CD20 monoclonal antibodies have become the backbone in the treatment of chronic lymphocytic leukemia (CLL). Historically, these antibodies were typically combined with chemotherapeutic agents. At present, therapeutic outcomes are significantly improving with the introduction of several novel targeted drugs to the clinical repertoire. AREAS COVERED:In this review, we summarize the current clinical standard together with the latest developments in the field of anti-CD20 antibodies against CLL. In addition, novel promising drugs against CLL are discussed, as well as their potential for combination with anti-CD20 monoclonal antibodies. EXPERT OPINION:At present, there are three different anti-CD20 monoclonal antibodies approved for the treatment of CLL with diverse effector mechanisms. These antibodies provide a robust foundation for combination therapy with novel molecules. Current research should be focused on reducing toxicity and reaching long-lasting remissions. There is still much to gain regarding the optimization of treatment combinations and dosing schedules for CLL. Overcoming the limitations of currently used anti-CD20 antibodies will be critical to further improve the efficacy of CLL therapy.
The applications of anti-CD20 antibodies to treat various B cells disorders.
Payandeh Zahra,Bahrami Armina Alagheband,Hoseinpoor Reyhaneh,Mortazavi Yousef,Rajabibazl Masoumeh,Rahimpour Azam,Taromchi Amir Hossein,Khalil Saeed
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
B-lymphocyte antigen CD20 (called CD20) is known as an activated-glycosylated phosphoprotein which is expressed on the surface of all B-cells. CD20 is involved in the regulation of trans-membrane Ca conductance and also play critical roles in cell-cycle progression during human B cell proliferation and activation. The appearance of monoclonal antibody (mAb) technology provided an effective field for targeted therapy in treatment of a variety of diseases such as cancer, and autoimmune diseases. Anti-CD20 is one of important antibodies which could be employed in treatment of several diseases. Increasing evidences revealed that efficacy of different anti-CD20 antibodies is implicated by their function. Hence, evaluation of anti-CD20 antibodies function could provide and introduce new anti-CD20 based therapies. In the present study, we summarized several applications of anti-CD20 antibodies in various immune related disorders including B-CLL (B-cell chronic lymphocytic leukemia), rheumatoid arthritis (RA), multiple sclerosis (MS) and melanoma.
Rituximab as a therapeutic option for patients with advanced melanoma.
Winkler Julia K,Schiller Matthias,Bender Carolin,Enk Alexander H,Hassel Jessica C
Cancer immunology, immunotherapy : CII
Treatment of metastatic melanoma remains challenging, despite a variety of new and promising immunotherapeutic and targeted approaches to therapy. New treatment options are still needed to improve long-term tumour control. We present a case series of seven patients with metastatic melanoma who were treated individually with the anti-CD20 antibody rituximab between July 2014 and July 2015. Two of the patients were treated in an adjuvant setting. All patients had already received a variety of treatments. During an induction phase, the administration of four cycles of weekly rituximab 375 mg/m body surface area was planned. After imaging, patients with stable disease continued therapy with rituximab 375 mg/m body surface area every 4 weeks up to a maximum of 24 weeks. Two patients experienced grade 2 infusion reactions during the first infusion. Otherwise, treatment was well tolerated and there were no grade 3 or 4 side effects. Staging after the induction phase showed stable disease in five patients, and two patients had progressive disease. Median progression-free survival was 6.3 months (95% CI 4.97-7.53), median overall survival was 14.7 months (95% CI 4.52-24.94), and one patient was still alive in December 2016. In conclusion, rituximab might be a therapeutic option for metastatic melanoma. However, further studies on rituximab among larger patient cohorts are warranted. Evaluation of therapy in an adjuvant setting or in combination with other systemic treatment might, therefore, be of particular interest.
Rituximab in systemic autoimmune rheumatic diseases: indications and practical use.
Berghen Nathalie,Vulsteke Jean-Baptiste,Westhovens Rene,Lenaerts Jan,De Langhe Ellen
Acta clinica Belgica
To review the therapeutic option of Rituximab, a chimeric anti-CD20 antibody, in systemic autoimmune rheumatic diseases (SARDs) such as systemic lupus erythematosus, systemic sclerosis, primary Sjögren syndrome and idiopathic inflammatory myopathy. A non-systematic review was conducted. The specific role and indication of rituximab in SARDs has been the subject of multiple trials in recent years. Evidence supports the use of rituximab in moderate-to-severe refractory systemic lupus erythematosus, diffuse skin involvement in systemic sclerosis and systemic involvement in primary Sjögren syndrome. Several guidelines have adopted these indications. In addition, there is a consensus about the use of rituximab in refractory myositis. The role of rituximab in interstitial lung disease associated with these SARDs needs to be further explored. Rituximab is a treatment option in several SARDs. Upcoming trials, use in daily practice and the safety profile are elaborated on.