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Nature Reviews. Drug Discovery Aug 2023Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of highly cytotoxic agents, potentially reducing the severity of side... (Review)
Review
Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of highly cytotoxic agents, potentially reducing the severity of side effects by preferentially targeting their payload to the tumour site. ADCs are being increasingly used in combination with other agents, including as first-line cancer therapies. As the technology to produce these complex therapeutics has matured, many more ADCs have been approved or are in late-phase clinical trials. The diversification of antigenic targets as well as bioactive payloads is rapidly broadening the scope of tumour indications for ADCs. Moreover, novel vector protein formats as well as warheads targeting the tumour microenvironment are expected to improve the intratumour distribution or activation of ADCs, and consequently their anticancer activity for difficult-to-treat tumour types. However, toxicity remains a key issue in the development of these agents, and better understanding and management of ADC-related toxicities will be essential for further optimization. This Review provides a broad overview of the recent advances and challenges in ADC development for cancer treatment.
Topics: Humans; Immunoconjugates; Antineoplastic Agents; Neoplasms; Antibodies, Monoclonal; Tumor Microenvironment
PubMed: 37308581
DOI: 10.1038/s41573-023-00709-2 -
Journal of Pharmaceutical Sciences Dec 2023Antibody-drug conjugates unite the specificity and long circulation time of an antibody with the toxicity of a chemical cytostatic or otherwise active drug using... (Review)
Review
Antibody-drug conjugates unite the specificity and long circulation time of an antibody with the toxicity of a chemical cytostatic or otherwise active drug using appropriate chemical linkers to reduce systemic toxicity and increase therapeutic index. This combination of a large biological molecule and a small molecule creates an increase in complexity. Multiple production processes are required to produce the native antibody, the drug and the linker, followed by conjugation of afore mentioned entities to form the final antibody-drug conjugate. The connected processes further increase the number of points of control, resulting in necessity of additional specifications and intensified analytical characterization. By combining scientific understanding of the production processes with risk-based approaches, quality can be demonstrated at those points where control is required and redundant comparability studies, specifications or product characterization are avoided. Over the product development lifecycle, this will allow process qualification to focus on those areas critical to quality and prevent redundant studies. The structure of the module 3 common technical document for an ADC needs to reflect each of the production processes and the combined overall approach to quality. Historically, regulatory authorities have provided varied expectations on its structure. This paper provides an overview of essential information to be included and shows that multiple approaches work as long as adequate cross-referencing is included.
Topics: Immunoconjugates; Antibodies, Monoclonal
PubMed: 37741455
DOI: 10.1016/j.xphs.2023.09.007 -
MAbs 2024The 'Antibodies to Watch' article series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical...
The 'Antibodies to Watch' article series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those recently granted a first approval in any country. In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi)). We briefly review 26 product candidates for which marketing applications are under consideration in at least one country or region, and 23 investigational antibody therapeutics that are forecast to enter regulatory review by the end of 2024 based on company disclosures. These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa). We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutic development efforts by the biopharmaceutical industry are robust and increasingly successful.
Topics: Antineoplastic Agents; Trastuzumab; Immunoconjugates; Biological Products
PubMed: 38178784
DOI: 10.1080/19420862.2023.2297450 -
Hematology. American Society of... Dec 2023Management of hematological malignancies is rapidly evolving from chemotherapy-based regimens toward targeted agents and immunotherapies, including bispecific antibodies... (Review)
Review
Management of hematological malignancies is rapidly evolving from chemotherapy-based regimens toward targeted agents and immunotherapies, including bispecific antibodies (BsAbs). These novel and highly active treatments come with new side effect profiles. The hematological toxicities are common and potentially harmful, and the side effects have hitherto not been reviewed. With many BsAbs recently approved and entering routine clinical use, we have reviewed the rather limited published data and propose recommendations on the management of these toxicities. Our review of the available data confirms that hematological toxicities are among the most common toxicities, with potentially harmful consequences for the patients. Fortunately, hemophagocytic lymphohystiocytosis and disseminated intravascular coagulation are rare. Severe neutropenia and hypogammaglobulinemia are manageable, and their timely treatment and prevention may reduce morbidity and mortality.
Topics: Humans; Antibodies, Bispecific; Radioimmunotherapy; Hematologic Neoplasms; Immunotherapy
PubMed: 38066890
DOI: 10.1182/hematology.2023000508 -
Nephrology, Dialysis, Transplantation :... Feb 2024Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN... (Review)
Review
Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN has evolved, with the identification of specific autoantibodies against novel podocyte antigens and the unraveling of intricate pathogenic pathways. Although the anti-CD20 monoclonal antibody rituximab is favored as part of the initial therapy in MN, a subgroup of MN patients may be resistant to rituximab necessitating the use of alternative agents such as cytotoxic therapies. In addition, newer agents such as novel anti-CD20 monoclonal antibodies, therapies targeting the CD38-positive plasma cells and anti-complement therapy are being studied in patients who are resistant to traditional treatment strategies. This manuscript furnishes a review of the novel developments in the pathophysiology of MN including the identification of target antigens and current treatment standards for MN, concentrating on evidenced-based interventions designed to attain remission and to prevent disease progression.
Topics: Humans; Glomerulonephritis, Membranous; Rituximab; Antibodies, Monoclonal; Autoantibodies; Antigen-Antibody Complex; Receptors, Phospholipase A2
PubMed: 37934599
DOI: 10.1093/ndt/gfad225 -
Annual Review of Medicine Jan 2024Multiple myeloma is a cancer of bone marrow plasma cells that represents approximately 10% of hematologic malignancies. Though it is typically incurable, a remarkable... (Review)
Review
Multiple myeloma is a cancer of bone marrow plasma cells that represents approximately 10% of hematologic malignancies. Though it is typically incurable, a remarkable suite of new therapies developed over the last 25 years has enabled durable disease control in most patients. This article briefly introduces the clinical features of multiple myeloma and aspects of multiple myeloma biology that modern therapies exploit. Key current and emerging treatment modalities are then reviewed, including cereblon-modulating agents, proteasome inhibitors, monoclonal antibodies, other molecularly targeted therapies (selinexor, venetoclax), chimeric antigen receptor T cells, T cell-engaging bispecific antibodies, and antibody-drug conjugates. For each modality, mechanism of action and clinical considerations are discussed. These therapies are combined and sequenced in modern treatment pathways, discussed at the conclusion of the article, which have led to substantial improvements in outcomes for multiple myeloma patients in recent years.
Topics: Humans; Multiple Myeloma; Immunotherapy; Proteasome Inhibitors; Antibodies, Monoclonal; Biological Therapy
PubMed: 37729027
DOI: 10.1146/annurev-med-050522-033815 -
Journal of Neurology Aug 2023New diagnostic criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) have recently been proposed, distinguishing this syndrome from other... (Review)
Review
New diagnostic criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) have recently been proposed, distinguishing this syndrome from other inflammatory diseases of the central nervous system. Seropositivity status for MOG-IgG autoantibodies is important for diagnosing MOGAD, but only in the context of robust clinical characterization and cautious interpretation of neuroimaging. Over the last several years, access to cell-based assay (CBA) techniques has improved diagnostic accuracy, yet the positive predictive value of serum MOG-IgG values varies with the prevalence of MOGAD in any given patient population. For this reason, possible alternative diagnoses need to be considered, and low MOG-IgG titers need to be carefully weighted. In this review, cardinal clinical features of MOGAD are discussed. Key challenges to the current understanding of MOGAD are also highlighted, including uncertainty regarding the specificity and pathogenicity of MOG autoantibodies, the need to identify immunopathologic targets for future therapies, the quest to validate biomarkers that facilitate diagnosis and detect disease activity, and the importance of deciphering which patients with MOGAD require long-term immunotherapy.
Topics: Humans; Myelin-Oligodendrocyte Glycoprotein; Autoantibodies; Central Nervous System; Immunotherapy; Immunoglobulin G; Aquaporin 4; Neuromyelitis Optica
PubMed: 37154894
DOI: 10.1007/s00415-023-11737-8 -
Cell Nov 2023Drug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for alternative therapeutic approaches. Here, we deciphered the B...
Drug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for alternative therapeutic approaches. Here, we deciphered the B cell and antibody response to the virulence-associated type III secretion system (T3SS) in a cohort of patients chronically infected with PA. Single-cell analytics revealed a diverse B cell receptor repertoire directed against the T3SS needle-tip protein PcrV, enabling the production of monoclonal antibodies (mAbs) abrogating T3SS-mediated cytotoxicity. Mechanistic studies involving cryoelectron microscopy identified a surface-exposed C-terminal PcrV epitope as the target of highly neutralizing mAbs with broad activity against drug-resistant PA isolates. These anti-PcrV mAbs were as effective as treatment with conventional antibiotics in vivo. Our study reveals that chronically infected patients represent a source of neutralizing antibodies, which can be exploited as therapeutics against PA.
Topics: Humans; Antibodies, Bacterial; Cryoelectron Microscopy; Immunoglobulins; Pseudomonas aeruginosa; Antibodies, Neutralizing; Pseudomonas Infections
PubMed: 37918395
DOI: 10.1016/j.cell.2023.10.002 -
The Journal of Clinical Investigation Sep 2023Antibody-drug conjugates (ADCs) have emerged as a revolutionary therapeutic class, combining the precise targeting ability of monoclonal antibodies with the potent... (Review)
Review
Antibody-drug conjugates (ADCs) have emerged as a revolutionary therapeutic class, combining the precise targeting ability of monoclonal antibodies with the potent cytotoxic effects of chemotherapeutics. Notably, ADCs have rapidly advanced in the field of breast cancer treatment. This innovative approach holds promise for strengthening the immune system through antibody-mediated cellular toxicity, tumor-specific immunity, and adaptive immune responses. However, the development of upfront and acquired resistance poses substantial challenges in maximizing the effectiveness of these therapeutics, necessitating a deeper understanding of the underlying mechanisms. These mechanisms of resistance include antigen loss, derangements in ADC internalization and recycling, drug clearance, and alterations in signaling pathways and the payload target. To overcome resistance, ongoing research and development efforts are focused on urgently identifying biomarkers, integrating immune therapy approaches, and designing novel cytotoxic payloads. This Review provides an overview of the mechanisms and clinical effectiveness of ADCs, and explores their unique immune-boosting function, while also highlighting the complex resistance mechanisms and safety challenges that must be addressed. A continued focus on how ADCs impact the tumor microenvironment will help to identify new payloads that can improve patient outcomes.
Topics: Humans; Female; Breast Neoplasms; Antibodies, Monoclonal; Immunoconjugates; Immunity; Tumor Microenvironment
PubMed: 37712425
DOI: 10.1172/JCI172156 -
Nature Reviews. Cancer Jun 2024The greatest challenge in cancer therapy is to eradicate cancer cells with minimal damage to normal cells. Targeted therapy has been developed to meet that challenge,... (Review)
Review
The greatest challenge in cancer therapy is to eradicate cancer cells with minimal damage to normal cells. Targeted therapy has been developed to meet that challenge, showing a substantially increased therapeutic index compared with conventional cancer therapies. Antibodies are important members of the family of targeted therapeutic agents because of their extraordinarily high specificity to the target antigens. Therapeutic antibodies use a range of mechanisms that directly or indirectly kill the cancer cells. Early antibodies were developed to directly antagonize targets on cancer cells. This was followed by advancements in linker technologies that allowed the production of antibody-drug conjugates (ADCs) that guide cytotoxic payloads to the cancer cells. Improvement in our understanding of the biology of T cells led to the production of immune checkpoint-inhibiting antibodies that indirectly kill the cancer cells through activation of the T cells. Even more recently, bispecific antibodies were synthetically designed to redirect the T cells of a patient to kill the cancer cells. In this Review, we summarize the different approaches used by therapeutic antibodies to target cancer cells. We discuss their mechanisms of action, the structural basis for target specificity, clinical applications and the ongoing research to improve efficacy and reduce toxicity.
Topics: Humans; Neoplasms; Immunoconjugates; Antibodies, Bispecific; Animals; T-Lymphocytes; Antineoplastic Agents, Immunological
PubMed: 38740967
DOI: 10.1038/s41568-024-00690-x