Immunogenicity of monoclonal antibody: Causes, consequences, and control strategies.
Pathology, research and practice
Antibody-based treatment was first used in 1891 for the treatment of diphtheria. Since then, monoclonal antibodies (mAbs) have been developed to treat many diseases such as cancer and act as vaccines. However, murine-derived therapeutic mAbs were found to be highly immunogenic, and caused anti-drug antibodies (ADAs) reaction, reducing their efficacy and causing severe infusion reactions. Fully human, humanised, and chimeric antibodies were then introduced for better therapeutic efficacy. With the introduction of immune response associated with mAbs immunogenicity. This review explores the immunogenicity of mAbs, its mechanism, contributing factors, and its impact on therapeutic efficacy. It also discusses immunogenicity assessment for preclinical studies and strategies for minimising immunogenicity for effective therapeutic treatment in various diseases. Finally, predicting immunogenicity in drug development is essential for selecting top drug candidates. A lot of methods can be implemented by the researchers and developers to reduce the development of ADAs while simultaneously minimising the immunogenicity reaction of mAbs.
10.1016/j.prp.2024.155627
Antibody-targeted T cells and natural killer cells for cancer immunotherapy.
Journal of nanobiotechnology
BACKGROUND:Adoptive cell cancer therapies aim to re-engineer a patient's immune cells to mount an anti-cancer response. Chimeric antigen receptor T and natural killer cells have been engineered and proved successful in treating some cancers; however, the genetic methods for engineering are laborious, expensive, and inefficient and can cause severe toxicities when they over-proliferate. RESULTS:We examined whether the cell-killing capacity of activated T and NK cells could be targeted to cancer cells by anchoring antibodies to their cell surface. Using metabolic glycoengineering to introduce azide moieties to the cellular surface, we covalently attached a dibenzocyclooctyne-modified antibody using the strain-promoted alkyne azide cycloaddition reaction, creating antibody-conjugated T and NK cells. We targeted the immune cells to tumors possessing the xenoantigen, N-glycolyl neuraminic acid GM3 ganglioside, using the 14F7hT antibody. These activated T and NK cells are "armed" with tumour-homing capabilities that specifically lyses antigen-positive cancer cells without off-target toxicities. Moreover, when exposed to target cells, 14F7hT-conjugated T cells that are not preactivated exhibit increased perforin, granzyme, CD69, and CD25 expression and specific cell killing. CONCLUSIONS:This research shows the potential for a non-genetic method for redirecting cytotoxic immune cells as a feasible and effective approach for tumor-targeted cell immunotherapy.
10.1186/s12951-024-02898-3
Antibody and cellular immunotherapies for acute lymphoblastic leukemia in adults.
Leukemia & lymphoma
Despite improvements in the outcomes of patients with acute lymphoblastic leukemia (ALL), traditional therapies (including hematopoietic stem cell transplant) often still fail. Antigen-specific immunotherapies for the treatment of ALL such as monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cells have demonstrated remarkable clinical efficacy and are rapidly evolving. With indisputable activity in patients with relapsed or refractory ALL, efforts now hope to integrate these agents into earlier phases of treatment. In this review, we will discuss the available antibody and cellular-based immunotherapies for the treatment of patients with ALL and provide a clinical and biologic framework with which to inform treatment approaches.
10.1080/10428194.2021.1964022
Neutropaenia complications from Ocrelizumab and Rituximab treatment.
Multiple sclerosis and related disorders
Ocrelizumab is an anti-CD20 monoclonal antibody (mAb) that has been shown in phase 3 clinical trials to reduce relapses and disease progression in multiple sclerosis (MS) patients. Prior to the approval of ocrelizumab, rituximab, a chimeric anti-CD20 mAb was used to treat MS. Rituximab is still used to treat MS in many countries outside of Australia and remains mainstay of treatment of many non-MS neuroimmunological and systemic inflammatory diseases. Rituximab is currently used in neuromyelitis optica spectrum disorder (NMOSD) and autoimmune encephalitis, in addition to its widespread usage in hematological malignancies and systemic inflammatory diseases. Ocrelizumab is currently approved in Australia for treatment of relapsing-remitting MS (RRMS). Neutropaenia is a rare complication of both ocrelizumab and rituximab treatment. This case series reports 12 patients who have experienced neutropaenia following ocrelizumab or rituximab treatment and aims to characterize the clinical parameters of neutropaenia experienced by these patients, including the severity and duration of neutropaenia, length of hospital admission, the types of subsequent infections experienced and types of treatment necessary before patients reached count recovery. The unpredictability of neutropaenia and potential for serious infections highlight the need for continued hematological monitoring for patients on B-cell depleting therapies and calls for careful patient counselling to provide guidance on whether to continue such therapies in patients who have experienced related neutropaenia.
10.1016/j.msard.2023.105147
CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus.
Arthritis & rheumatology (Hoboken, N.J.)
B cell generation of autoantibodies is a crucial step in the pathogenesis of systemic lupus erythematosus (SLE). After their differentiation in the bone marrow, B cells populate the secondary lymphatic organs, where they undergo further maturation leading to the development of memory B cells as well as antibody-producing plasmablasts and plasma cells. Targeting B cells is an important strategy to treat autoimmune diseases such as SLE, in which B cell tolerance is disturbed and autoimmune B cells and autoantibodies emerge. This review discusses the functional aspects of antibody- and cell-based B cell-depleting therapy in SLE. It thereby particularly focuses on lessons learned from chimeric antigen receptor (CAR) T cell treatment on the role of B cells in SLE for understanding B cell pathology in SLE. CAR T cells model a deep B cell depletion and thereby allow understanding the role of aberrant B cell activation in the pathogenesis of SLE. Furthermore, the effects of B cell depletion on autoantibody production can be better described, ie, explaining the concept of different cellular sources of (auto-) antibodies in the form of short-lived plasmablasts and long-lived plasma cells, which differ in their susceptibility to B cell depletion and require different targeted therapeutic approaches. Finally, the safety of deep B cell depletion in autoimmune disease is discussed.
10.1002/art.42784
Update on the Application of Monoclonal Antibody Therapy in Primary Membranous Nephropathy.
Drugs
When first introduced, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, brought about an alternative therapeutic paradigm for primary membranous nephropathy (PMN). Rituximab was shown to be effective and safe in PMN patients with kidney dysfunction, with. patients receiving second-line rituximab therapy achieving remission as effectively as those patients who had not previously received immunotherapy. No safety issues were reported. The B cell-driven protocol seems to be as efficient as the 375 mg/m × 4 regimen or 1 g × 2 regimen in achieving B cell depletion and remission, but patients with high M-type phospholipase A2 receptor (PLA2R) antibody levels may benefit from a higher dose of rituximab. While rituximab added another therapeutic option to the treatment regimen, it does have limitations as 20 to 40% of patients do not respond. Not all patients respond to RTX therapy for lymphoproliferative disorders either, therefore further novel anti-CD20 monoclonal antibodies have been developed and these may provide alternative therapeutic options for PMN. Ofatumumab, a fully human monoclonal antibody, specifically recognizes an epitope encompassing both the small and large extracellular loops of the CD20 molecule, resulting in increased complement-dependent cytotoxic activity. Ocrelizumab binds an alternative but overlapping epitope region to rituximab and displays enhanced antibody-dependent cellular cytotoxic (ADCC) activities. Obinutuzumab is designed to have a modified elbow-hinge amino acid sequence, leading to increased direct cell death induction and ADCC activities. In PMN clinical studies, ocrelizumab and obinutuzumab showed promising results, while ofatumumab displayed mixed results. However, there is a lack of randomized controlled trials with large samples, especially direct head-to-head comparisons. Alternative molecular mechanisms have been suggested in this context to explore novel therapeutic strategies. B cell activator-targeted, plasma cell-targeted and complement-directed treatments may lead to novel therapy paradigms for PMN. Exploratory strategies for the use of drugs with different mechanisms, such as a combination of rituximab and cyclophosphamide and a steroid, a combination of rituximab and a calcineurin inhibitor, may provide more rapid and efficient remission, but the combination of standard immunosuppression with rituximab could increase infection risk.
10.1007/s40265-023-01855-y
Anti-inflammatory clearance of amyloid-β by a chimeric Gas6 fusion protein.
Nature medicine
Clearing amyloid-β (Aβ) through immunotherapy is one of the most promising therapeutic approaches to Alzheimer's disease (AD). Although several monoclonal antibodies against Aβ have been shown to substantially reduce Aβ burden in patients with AD, their effects on improving cognitive function remain marginal. In addition, a significant portion of patients treated with Aβ-targeting antibodies experience brain edema and microhemorrhage associated with antibody-mediated Fc receptor activation in the brain. Here, we develop a phagocytosis inducer for Aβ consisting of a single-chain variable fragment of an Aβ-targeting monoclonal antibody fused with a truncated receptor binding domain of growth arrest-specific 6 (Gas6), a bridging molecule for the clearance of dead cells via TAM (TYRO3, AXL, and MERTK) receptors. This chimeric fusion protein (αAβ-Gas6) selectively eliminates Aβ plaques through TAM receptor-dependent phagocytosis without inducing NF-kB-mediated inflammatory responses or reactive gliosis. Furthermore, αAβ-Gas6 can induce synergistic clearance of Aβ by activating both microglial and astrocytic phagocytosis, resulting in better behavioral outcomes with substantially reduced synapse elimination and microhemorrhage in AD and cerebral amyloid angiopathy model mice compared with Aβ antibody treatment. Our results suggest that αAβ-Gas6 could be a novel immunotherapeutic agent for AD that overcomes the side effects of conventional antibody therapy.
10.1038/s41591-022-01926-9
New and Old Anti-CD20 Monoclonal Antibodies for Nephrotic Syndrome. Where We Are?
Frontiers in immunology
Nephrotic proteinuria is the hallmark of several glomerulonephritis determined by different pathogenetic mechanisms, including autoimmune, degenerative and inflammatory. Some conditions such as Minimal Change Nephropathy (MCN) and Focal Segmental Glomerulosclerosis (FSGS) are of uncertain pathogenesis. Chimeric anti-CD20 monoclonal antibodies have been used with success in a part of proteinuric conditions while some are resistant. New human and humanized monoclonal anti-CD 20 antibodies offer some advantages based on stronger effects on CD20 cell subtypes and have been already administered in hematology and oncology areas as substitutes of chimeric molecules. Here, we revised the literature on the use of human and humanized anti-CD 20 monoclonal antibodies in different proteinuric conditions, resulting effective in those conditions resistant to rituximab. Literature on the use of human anti-CD 20 monoclonal antibodies in different proteinuric diseases is mainly limited to ofatumumab, with several protocols and doses. Studies already performed with ofatumumab given in standard doses of 1,500 mg 1.73m suggest no superiority compared to rituximab in children and young adults with steroid dependent nephrotic syndrome. Ofatumumab given in very high doses (300 mg/1.73m followed by five infusion 2,000 mg/1.73 m) seems more effective in patients who are not responsive to common therapies. The question of dose remains unresolved and the literature is not concordant on positive effects of high dose ofatumumab in patients with FSGS prior and after renal transplantation. Obinutuzumab may offer some advantages. In the unique study performed in patients with multidrug dependent nephrotic syndrome reporting positive effects, obinutuzumab was associated with the anti-CD38 monoclonal antibody daratumumab proposing the unexplored frontier of combined therapies. Obinutuzumab represent an evolution also in the treatment of autoimmune glomerulonephritis, such as membranous nephrotahy and lupus nephritis. Results of randomized trials, now in progress, are awaited to add new possibilities in those cases that are resistant to other drugs. The aim of the present review is to open a discussion among nephrologists, with the hope to achieve shared approaches in terms of type of antibodies and doses in the different proteinuric renal conditions.
10.3389/fimmu.2022.805697
Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals.
Drugs
Myasthenia gravis (MG) is a chronic, fluctuating, antibody-mediated autoimmune disorder directed against the post-synaptic neuromuscular junctions of skeletal muscles, resulting in a wide spectrum of manifestations ranging from mild to potentially fatal. Given its unique natural course, designing an ideal trial design for MG has been wrought with difficulties and evidence in favour of several of the conventional agents is weak as per current standards. Despite this, acetylcholinesterases and corticosteroids have remained the cornerstones of treatment for several decades with intravenous immunoglobulins (IVIG) and therapeutic plasma exchange (PLEX) offering rapid treatment response, especially in crises. However, the treatment of MG entails long-term immunosuppression and conventional agents are viable options but take longer to act and have a number of class-specific adverse effects. Advances in immunology, translational medicine and drug development have seen the emergence of several newer biological agents which offer selective, target-specific immunotherapy with fewer side effects and rapid onset of action. Eculizumab is one of the newer agents that belong to the class of complement inhibitors and has been approved for the treatment of refractory general MG. Zilucoplan and ravulizumab are other agents in this group in clinical trials. Neisseria meningitis is a concern with all complement inhibitors, mandating vaccination. Neonatal Fc receptor (FcRn) inhibitors prevent immunoglobulin recycling and cause rapid reduction in antibody levels. Efgartigimod is an FcRn inhibitor recently approved for MG treatment, and rozanolixizumab, nipocalimab and batoclimab are other agents in clinical trial development. Although lacking high quality evidence from randomized clinical trials, clinical experience with the use of anti-CD20 rituximab has led to its use in refractory MG. Among novel targets, interleukin 6 (IL6) inhibitors such as satralizumab are promising and currently undergoing evaluation. Cutting-edge therapies include genetically modifying T cells to recognise chimeric antigen receptors (CAR) and chimeric autoantibody receptors (CAAR). These may offer sustained and long-term remissions, but are still in very early stages of evaluation. Hematopoietic stem cell transplantation (HSCT) allows immune resetting and offers sustained remission, but the induction regimens often involve serious systemic toxicity. While MG treatment is moving beyond conventional agents towards target-specific biologicals, lack of knowledge as to the initiation, maintenance, switching, tapering and long-term safety profile necessitates further research. These concerns and the high financial burden of novel agents may hamper widespread clinical use in the near future.
10.1007/s40265-022-01726-y
Treatment strategies for patients with diffuse large B-cell lymphoma.
Cancer treatment reviews
Diffuse large B-cell lymphoma (DLBCL) is nowadays a curable disease with the frontline treatment R-CHOP, but 30-40% of patients are still unresponsive or relapse thereafter. In the recent era several upcoming new options are improving the therapeutic landscape for relapsed/refractory (R/R) DLBCL setting, first of all anti-CD19 chimeric antigen receptor T-cells (CAR-T) that already represent a standard of care as third-line therapy and are rapidly moving as second-line treatment for those who are refractory or early relapse after R-CHOP. Among these new therapies, the combinations polatuzumab plus rituximab and bendamustine, tafasitamab plus lenalidomide for transplant ineligible patients, and CD3xCD20 bispecific antibodies are the most relevant, but several other agents and strategies are on the way. On the other hand, in the last 20 years, several efforts have been spent in the attempt to ameliorate the outcome over R-CHOP for the frontline treatment of DLBCL shortening the interval between the cycles or intensifying treatment or adding novel drugs to R-CHOP without success, so far. Recent studies combining the anti-CD79b antibody-drug conjugate polatuzumab vedotin plus R-CHP and the anti-BCL2 agent venetoclax plus R-CHOP showed promising results. Preliminary data of new upcoming strategies characterized by a tailored therapy based on different molecular subtypes of DLBCL are encouraging, showing a benefit over the standard R-CHOP. In this manuscript, the literature data on the landscape of new therapies available and upcoming for both frontline and R/R settings of DLBCL will be critically reviewed.
10.1016/j.ctrv.2022.102443
Nanobodies in cancer.
Verhaar Elisha R,Woodham Andrew W,Ploegh Hidde L
Seminars in immunology
For treatment and diagnosis of cancer, antibodies have proven their value and now serve as a first line of therapy for certain cancers. A unique class of antibody fragments called nanobodies, derived from camelid heavy chain-only antibodies, are gaining increasing acceptance as diagnostic tools and are considered also as building blocks for chimeric antigen receptors as well as for targeted drug delivery. The small size of nanobodies (∼15 kDa), their stability, ease of manufacture and modification for diverse formats, short circulatory half-life, and high tissue penetration, coupled with excellent specificity and affinity, account for their attractiveness. Here we review applications of nanobodies in the sphere of tumor biology.
10.1016/j.smim.2020.101425
Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy.
Journal of medicinal chemistry
Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via co-opted ubiquitin ligases have enormous potential to transform the field of medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) in the chemical literature, enable the controlled degradation of specific proteins via their direction to the cellular proteasome. In this report, we describe the second phase of our research focused on exploring antibody-drug conjugates (ADCs), which incorporate BRD4-targeting chimeric degrader entities. We employ a new BRD4-binding fragment in the construction of the chimeric ADC payloads that is significantly more potent than the corresponding entity utilized in our initial studies. The resulting BRD4-degrader antibody conjugates exhibit potent and antigen-dependent BRD4 degradation and antiproliferation activities in cell-based experiments. Multiple ADCs bearing chimeric BRD4-degrader payloads also exhibit strong, antigen-dependent antitumor efficacy in mouse xenograft assessments that employ several different tumor models.
10.1021/acs.jmedchem.0c01846
Anti CD38 monoclonal antibodies for multiple myeloma treatment.
Human vaccines & immunotherapeutics
CD38 is a transmembrane glycoprotein with ectoenzymatic activity and is highly and uniformly expressed on multiple myeloma (MM) cells. CD38 is expressed also at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of non-hematopoietic origin. The specificity of this target has increased interest in new drugs and triggered the development of the CD38 monoclonal antibodies Daratumumab (fully human) and Isatuximab (chimeric). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38+ immune-suppressor cells. Monoclonal antibody-based therapy has revolutionized MM therapy in the latest years increasing depth of response. This product review will focus on anti-CD38 monoclonal antibodies Daratumumab and Isatuximab efficacy, safety, pharmacokinetic and pharmacodynamic data from clinical trials.
10.1080/21645515.2022.2052658
Lebrikizumab: First Approval.
Drugs
Lebrikizumab (Ebglyss) is a subcutaneous recombinant humanized IgG4 anti-IL-13 monoclonal antibody developed by Almirall S.A. and Eli Lilly and Company for the treatment of atopic dermatitis (AD). In November 2023, lebrikizumab was approved in the EU for the treatment of moderate-to-severe AD in adults and adolescents 12 years and older with a body weight of at least 40 kg who are candidates for systemic therapy. Lebrikizumab was approved for the same indication in the UK in December 2023 and in Japan in January 2024. Lebrikizumab is under regulatory review for the treatment of AD in the USA, Switzerland and Australia. This article summarizes the milestones in the development of lebrikizumab leading to this first approval for AD.
10.1007/s40265-024-02000-z