mAbs最新文献

Monoclonal antibodies (mAbs) and mAb-derived biologics have achieved substantial success across various therapeutic areas over recent decades. Their widespread adoption, however, remains constrained due to high prices and challenges in supply. Here, we examine the general price and cost structure of mAbs and mAb-derived therapeutics and identify directions to improve affordability and strategies to ensure supply. Mainstream and emerging biomanufacturing formats and their implications on cost and supply are discussed. We also summarize modeling tools used across industry for process economics analysis, emphasizing the importance of this assessment throughout the product development lifecycle. A comprehensive understanding of cost and supply scenarios will empower industry players to thrive despite competition, navigate supply challenges, and broaden access to mAb therapeutics for more patients.

Antibody repurposing is the process of changing a known antibody so that it binds to a mutated antigen. One of the findings to emerge from the Coronavirus Disease 2019 (COVID-19) pandemic was that it was possible to repurpose neutralizing antibodies for Severe Acute Respiratory Syndrome, a related disease, to work for COVID-19. Thus, antibody repurposing is a possible pathway to prepare for and respond to future pandemics, as well as personalizing cancer therapies. For antibodies to be successfully repurposed, it is necessary to know both how antigen mutations disrupt their binding and how they should be mutated to recover binding, with this work describing an analysis to address the first of these topics. Every possible antigen point mutation in the interface of 246 antibody-protein complexes were analyzed using the Rosetta molecular mechanics force field. The results highlight a number of features of how antigen mutations affect antibody binding, including the effects of mutating critical hotspot residues versus other positions, how many mutations are necessary to be likely to disrupt binding, the prevalence of indirect effects of mutations on binding, and the relative importance of changing attractive versus repulsive energies. These data are expected to be useful in guiding future antibody repurposing experiments.

Over the recent decades the market potential of biologics has substantially expanded, and many of the top-selling drugs worldwide are now monoclonal antibodies or antibody-like molecules. The common gamma chain (γc) cytokines, Interleukin (IL-)2, IL-4, IL-7, IL-9, IL-15, and IL-21, play pivotal roles in regulating immune responses, from innate to adaptive immunity. Dysregulation of cell signaling by these cytokines is strongly associated with a range of immunological disorders, which includes cancer as well as autoimmune and inflammatory diseases. Given the essential role of γc cytokines in maintaining immune homeostasis, the development of therapeutic interventions targeting these molecules poses unique challenges. Here, we provide an overview of current biologics targeting either single or multiple γc cytokines or their respective receptor subunits across a spectrum of diseases, primarily focusing on antibodies, antibody-like constructs, and antibody-cytokine fusions. We summarize therapeutic biologics currently in clinical trials, highlighting how they may offer advantages over existing therapies and standard of care, and discuss recent advances in this field. Finally, we explore future directions and the potential of novel therapeutic intervention strategies targeting this cytokine family.

In early-stage development of therapeutic monoclonal antibodies, assessment of the viability and ease of their purification typically requires extensive experimentation. However, the work required for upstream protein expression and downstream purification development often conflicts with timeline pressures and material constraints, limiting the number of molecules and process conditions that can reasonably be assessed. Recently, high-throughput batch-binding screen data along with improved molecular descriptors have enabled development of robust quantitative structure-property relationship (QSPR) models that predict monoclonal antibody chromatographic binding behavior from the amino acid sequence. Here, we describe a QSPR strategy for in silico monoclonal antibody purification process fit assessment. Principal Component Analysis is applied to extract a one-dimensional basis for comparison of molecular chromatographic binding behavior from multi-dimensional high-throughput batch-binding screen data. Kernel Ridge Regression is used to predict the first principal component for new molecular sequences. This workflow is demonstrated with a set of 97 monoclonal antibodies for five chromatography resins in two salt types across a range of pH and salt concentrations. Model development benchmarks four descriptor sets from biophysical structural models and protein language models. The investigation illustrates the value QSPR models can provide to purification process fit assessment, and selection of resins and operating conditions from sequence alone.

The commercial development of antibody therapeutics is a global enterprise involving thousands of biopharmaceutical firms and supporting service organizations. To date, their combined efforts have resulted in over 200 marketed antibody therapeutics and a pipeline of nearly 1,400 investigational product candidates that are undergoing evaluation in clinical studies as treatments for a wide variety of diseases. Here, we discuss key events in antibody therapeutics development that occurred during 2024 and forecast key events related to the late-stage clinical pipeline that may occur in 2025. In particular, we report on 21 antibody therapeutics granted a first approval in at least one country or region during 2024, including bispecific antibodies tarlatamab (IMDELLTRA®), zanidatamab (Ziihera®), zenocutuzumab (BIZENGRI®), odronextamab (Ordspono®), ivonescimab (®), and antibody-drug conjugate (ADC) sacituzumab tirumotecan (®). We also discuss 30 investigational antibody therapeutics for which marketing applications were undergoing review by at least one regulatory agency, as of our last update on December 9, 2024, including ADCs datopotamab deruxtecan, telisotuzumab vedotin, patritumab deruxtecan, trastuzumab botidotin, becotatug vedotin, and trastuzumab rezetecan. Of 178 antibody therapeutics we include in the late-stage pipeline, we summarize key data for 18 for which marketing applications may be submitted by the end of 2025, such as bi- or multispecific antibodies denecimig, sonelokimab, erfonrilimab, and anbenitamab. Key trends in the development and approval of antibody formats such as bispecifics and ADCs, as well as clinical-phase transition and global approval success rates for these antibody formats, are reported.

Immunogenic responses to biotherapeutics often lead to termination of their development because the resulting anti-drug-antibodies (ADA) can negatively impact pharmacology, safety, and efficacy. To mitigate ADA risks, in vitro risk assessment assays in non-clinical settings are essential to enhance safety and efficacy of protein-based therapeutics. This study aimed to develop and validate a human in vitro immunogenicity T cell proliferation assay. However, there is a lack of comprehensive guidelines for managing product-related factors such as endotoxin contamination, which can significantly influence assay sensitivity and accuracy. Our investigation of the impact of endotoxins revealed that levels above 0.1 EU/mg significantly induce T cell proliferation and CD14⁺ myeloid cell expansion, leading to potential false-positive outcomes in immunogenicity assessments. These findings suggest the importance of developing standardized protocols to enhance the predictive capability of in vitro methods, ensuring the assessment of therapeutic proteins accurately reflects their immunogenic potential without interference from contaminants.

Antibodies used for cancer therapy are monoclonal IgGs, but tumor-targeting IgE antibodies have shown enhanced effector cell potency against cancer in preclinical models. Research-grade recombinant IgE antibodies have been generated and studied for several decades. The recent Phase 1 clinical trial of the first-in-class MOv18 IgE, however, necessitated the inaugural process development and scaled manufacture of a recombinant IgE to clinical quality standards. During the process development and scaled Good Manufacturing Practice production, we demonstrate the retention of glycosylation state, biophysical profile, and functional characteristics of MOv18 IgE, including Fc-mediated mast cell degranulation and tumor cell killing. Assessment of manufacturing parameters shows expected pH, purity, concentration, and stability properties, as well as below threshold levels of known biological manufacturing contaminants. We confirm the suitability of the pipeline described for generating intact, functionally active, clinical-grade material for this novel therapeutic class as an Investigational Medicinal Product (IMP), with comparable characteristics to the original research-grade antibody. Furthermore, we screened patient blood ex vivo for potential type I hypersensitivity reaction to MOv18 IgE, using the basophil activation test, to identify patients not predicted to be hypersensitive to MOv18 IgE administration. This study supports the production of functionally active clinical grade (IMP) recombinant IgE and paves the way for the development of a new therapeutic antibody class for a range of antigenic specificities and disease settings.

The binding kinetics of an antibody for its target antigen represent key determinants of its biological function and success as a novel biotherapeutic. Defining these interactions and kinetics is critical for understanding the pharmacological and pharmacodynamic profiles of antibodies in therapeutic applications, with line of sight to clinical translation. In this review, we discuss the latest developments in approaches to measure and modulate antibody-antigen interactions, including antibody engineering, novel antibody formats, current, and emerging technologies for measuring antibody-antigen binding interactions, and emerging perspectives within the field. We also explore how emerging computational methods are set to become powerful tools for modeling antibody-binding interactions under physiologically relevant conditions. Finally, we consider the therapeutic implications of modulating target engagement in terms of pharmacodynamics and pharmacokinetics.

Over the past decades, the number of therapeutic protein pipelines in early-phase clinical studies has increased dramatically. The rapid growth in the pipeline underscores the need to accelerate early-stage development and enable fast first-in-human (FIH) trials to bring novel therapies to patients. Across the industry, various efforts have been developed to achieve this goal. In this communication, a platform analytical method validation approach developed and used by MSD for FIH programs is described. A case study from the release panel, a polysorbate 80 (PS-80) platform method is utilized to illustrate the workflow. In this approach, historical validation data within the same modality are summarized and supplemented with statistical analyses to justify a limited validation for future pipeline projects. The platform method validation strategy has reduced the overall validation timeline from up to 4 months to 1-2 months and has successfully been implemented in FIH filings. This communication provides insights to pharmaceutical companies interested in developing platform analytical method validation approaches for fast FIH studies.