Recent Advances in the Development of Monoclonal Antibodies and Next-Generation Antibodies

Singh, Rohit; Chandley, Pankaj; Rohatgi, Soma

doi:10.4049/immunohorizons.2300102

Cited by 11 publications

(3 citation statements)

References 104 publications

(104 reference statements)

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“…Commonly used monoclonal antibody screening technologies include traditional murine hybridoma fusion, transgenic mouse technology, single B cell isolation, cloning and phage display ( 69 ). The conventional murine hybridoma method yields antibodies derived from mice, which are susceptible to human anti-mouse antibody responses, limiting their clinical applicability.…”

Section: Current Status Of Preparation Methods and Development Of Nabsmentioning

confidence: 99%

Current development of severe acute respiratory syndrome coronavirus 2 neutralizing antibodies (Review)

Zhang,

Yang,

Tang

et al. 2024

Mol Med Rep

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Section: Current Status Of Preparation Methods and Development Of Nabsmentioning

confidence: 99%

Current development of severe acute respiratory syndrome coronavirus 2 neutralizing antibodies (Review)

Zhang,

Yang,

Tang

et al. 2024

Mol Med Rep

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“…There are still major medical needs to improve the efficacy of therapeutic mAbs. Modification of the effector functions using Fc bioengineering 9 or antibody drug-conjugation combining anticancer drug such as trastuzumab-emtansine (T-DM1) 10 are the main important approaches. The alternative pathway represents another critical component of the complement pathway that can be harnessed against tumor progression 11, 12 .…”

Section: Introductionmentioning

confidence: 99%

Complement-Activating Multimeric Immunotherapeutic Complexes for HER2-breast cancer immunotherapy

Seguin-Devaux,

Brandus,

Plesseria

et al. 2024

Preprint

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BackgroundDirecting selective complement activation towards tumor cells is an attractive strategy to promote their elimination. We have generated Complement-activating Multimeric immunotherapeutic compleXes (CoMiX) that selectively stimulate the alternative pathway using Factor H Related protein 4 (FHR4) or the classical complement pathways using triple Fc dimers on HER2-expressing tumor cells.MethodsWe used the C4bp C-terminal-α-/β-chain multimerising scaffolds to generate CoMiX-FHR4 and CoMiX-Fc with 2 different VHH anti-HER2, VHH(T) and VHH(P), recognising trastuzumab-or pertuzumab-competing HER2 epitopes, respectively: FHR4/VHH(T), FHR4/VHH(P), VHH(T)/Fc, VHH(P)/Fc. The different CoMiX were comparedin vitrofor C3b and C5b9 depositions, complement-dependent cytotoxicity, and their ability to activate NK cells and phagocytosis by macrophages using one-way ANOVA and post-hoc Tukey’s tests. We further explored their therapeutic efficacyin vivoon human BT474 breast cancer xenografts established in NUDE mice, when used individually or in combination, as compared to trastuzumab or pertuzumab.ResultsFHR4/VHH(T) and FHR4/VHH(P) led to the highest C3b and C5b9 depositions and CDC, both individually and in combinations on BT474 tumor cells (p< 0.0001) surpassing the very low complement activating capacity of trastuzumab and pertuzumab. CoMiX-Fc showed NK cell activation and complement-mediated BT474 phagocytosis by M2 macrophages. In the xenograft model, CoMiX-FHR4 molecules reduced the tumor volume by a factor of 7.33 compared to the PBS control. VHH(T)/Fc had no effect on tumor growth, while VHH(P)/Fc led to a 2.75-times tumor volume reduction that was higher than pertuzumab (p< 0.01). Trastuzumab and its combination with pertuzumab remained the most potent regimen, alone or in combination, to completely inhibit tumor growth. CoMiX-FHR4, CoMiX-Fc and C3b deposition were visualized as soon as one hour after injection resulting in a massive homogeneous complement deposit 6 hours after injection. Interestingly, CoMiX-FHR4 significantly reduced the growth of trastuzumab-resistant cancer cells in contrast to trastuzumab and induced a large NK cell infiltration into the tumor.ConclusionsCoMiX-FHR4 and CoMiX VHH(P)/Fc significantly inhibit tumor growth through complement activation, NK cells infiltration, and phagocytosis by macrophages. CoMiX-FHR4 proteins delay xenograft growth of BT474 cells resistant to trastuzumab and could thus be an attractive approach when resistance to antibody emerges.Key messagesWhat is already known on this topicComplement activation represents a substantial part of the overall biological activity of few therapeutic antibodies used in cancer immunotherapy. Factor H-related protein 4 can activate complement by serving as a platform for the assembly of alternative pathway C3 convertase by competing with factor H for C3b binding. We previously showed that multimeric recombinant proteins displaying the FHR4 complement effector moiety and a nanobody anti-HER2 targeting moiety selectively direct the activation of the complement alternative pathway on HER2-expressing tumor cells, leading to subsequent cell destruction through direct cell lysis or through the activation of host effector cells.What this study addsWe used in the current work a novel complement-directed tumor cell distruction strategyin vivo. We showed that CoMiX-FHR4 and CoMiX-Fc (based on triple Fc dimers), targeting HER2-positive breast tumor cells, inhibit tumor growth in a model of BT474 xenograft in NUDE mice by stimulating complement activation, BT474 death, NK cell activation, and phagocytosis of tumor cells by macrophages. CoMiX-FHR4 remain efficient in xenografts of BT474 cells resistant to trastuzumab.How this study might affect research, practice or policyWe demonstrate for the first time that directed complement activation on tumor cells is an alternative to therapeutic antibodies which is particularly promising when resistance to standard-of-care treatment occurs.

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“…Monoclonal antibodies have revolutionized medicine by offering highly effective treatments for various diseases, including cancer, autoimmune disorders, infectious diseases, and more. Their specificity and versatility make them invaluable diagnostic and treatment tools, providing clinicians with powerful options to combat complex medical challenges [3]. This comprehensive review explores monoclonal antibodies' evolution and the current landscape in modern medicine.…”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Review of Monoclonal Antibodies in Modern Medicine: Tracing the Evolution of a Revolutionary Therapeutic Approach

Kothari,

Wanjari,

Acharya

et al. 2024

Cureus

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Monoclonal antibodies (mAbs) have emerged as potent therapeutic agents, revolutionizing the landscape of modern medicine. This comprehensive review traces the evolution of mAbs from their inception to their current prominence, highlighting key milestones in their development and exploring their diverse therapeutic applications. Beginning with an overview of their molecular structure and mechanisms of action, we delve into the production and engineering of mAbs, including hybridoma technology and recombinant DNA techniques. Therapeutic applications across various medical disciplines, including cancer treatment, autoimmune diseases, and infectious diseases, are examined in detail, showcasing the significant clinical successes of mAbs. Furthermore, this review discusses the challenges and opportunities in manufacturing scalability, cost-effectiveness, and access to therapies. Looking ahead, the implications of mAbs in future research and clinical practice are explored, emphasizing the potential for next-generation mAbs, personalized medicine, and integration with emerging modalities such as immunotherapy and gene therapy. In conclusion, the evolution of monoclonal antibodies underscores their transformative impact on healthcare and their continued promise to advance the frontiers of medicine.

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Recent Advances in the Development of Monoclonal Antibodies and Next-Generation Antibodies

Cited by 11 publications

References 104 publications

Current development of severe acute respiratory syndrome coronavirus 2 neutralizing antibodies (Review)

Current development of severe acute respiratory syndrome coronavirus 2 neutralizing antibodies (Review)

Complement-Activating Multimeric Immunotherapeutic Complexes for HER2-breast cancer immunotherapy

A Comprehensive Review of Monoclonal Antibodies in Modern Medicine: Tracing the Evolution of a Revolutionary Therapeutic Approach

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