Not all therapeutic antibody isotypes are equal: the case of IgM <i>versus</i> IgG in Pertuzumab and Trastuzumab

Samsudin, Firdaus; Yeo, Joshua Yi; Gan, Samuel Ken‐En; Bond, Peter J.

doi:10.1039/c9sc04722k

Cited by 29 publications

(40 citation statements)

References 62 publications

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“…While IgM has clear superior avidity and agglutination effects over IgG, it is not a blanket rule that IgM can be leveraged upon to create better antigen binders. In one example, we found that the location of the epitope on the antigen to severely limit full IgM valency through steric hindrances where Pertuzumab-IgM is shown to be better Pertuzumab-IgG1, but not for Trastuzumab-IgM and Trastuzumab-IgG1 [ 32 ] due to epitope location in the same HER2 antigen. However, in this particular case, the large size of IgM was also advantageous for steric inhibition of HER2 dimerization, providing an advantage for IgM in such mechanistic inhibition.…”

Section: Introductionmentioning

confidence: 99%

Sagacity in antibody humanization for therapeutics, diagnostics and research purposes: considerations of antibody elements and their roles

Ling

Lua

Gan

2020

Antibody Therapeutics

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The humanization of antibodies for therapeutics is a critical process that can determine the success of antibody drug development. However, the science underpinning this process remains elusive with different laboratories having very different methods. Well-funded laboratories can afford automated high-throughput screening methods to derive their best binder utilizing a very expensive initial set of equipment affordable only to a few. Often within these high-throughput processes, only standard key parameters, such as production, binding and aggregation are analyzed. Given the lack of suitable animal models, it is only at clinical trials that immunogenicity and allergy adverse effects are detected through anti-human antibodies as per FDA guidelines. While some occurrences that slip through can be mitigated by additional desensitization protocols, such adverse reactions to grafted humanized antibodies can be prevented at the humanization step. Considerations such as better antibody localization, avoidance of unspecific interactions to superantigens and the tailoring of antibody dependent triggering of immune responses, the antibody persistence on cells, can all be preemptively considered through a holistic sagacious approach, allowing for better outcomes in therapy and for research and diagnostic purposes.

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Section: Introductionmentioning

confidence: 99%

Sagacity in antibody humanization for therapeutics, diagnostics and research purposes: considerations of antibody elements and their roles

Ling

Lua

Gan

2020

Antibody Therapeutics

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“…Another consideration is that the epitope of the antibody can also affect accessibility, so the type of antibody format utilized could impact antigen binding. This is exemplified by Samsudin et al, who modelled how hexamers of pertuzumab IgM antibodies were capable of utilizing all of their variable regions to bind HER2, but trastuzumab IgM becomes hindered by steric clashes due to the globular conformation of HER2 [29]. Similar steric observations were observed when pertuzumab IgM was compared to pertuzumab IgG.…”

Section: Antibody Selectionmentioning

confidence: 87%

Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective

et al. 2021

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Antibody-drug conjugates (ADCs) appear to be in a developmental boom, with five FDA approvals in the last two years and a projected market value of over $4 billion by 2024. Major advancements in the engineering of these novel cytotoxic drug carriers have provided a few early success stories. Although the use of these immunoconjugate agents are still in their infancy, valuable lessons in the engineering of these agents have been learned from both preclinical and clinical failures. It is essential to appreciate how the various mechanisms used to engineer changes in ADCs can alter the complex pharmacology of these agents and allow the ADCs to navigate the modern-day therapeutic challenges within oncology. This review provides a global overview of ADC characteristics which can be engineered to alter the interaction with the immune system, pharmacokinetic and pharmacodynamic profiles, and therapeutic index of ADCs. In addition, this review will highlight some of the engineering approaches being explored in the creation of the next generation of ADCs.

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“…polymorphonuclear cells 2 , 47 , 48 . IgM is also considered to have some inherent advantages as compared to IgG antibodies because IgM has high avidity binding to antigen and exhibits greater ability to utilize the complement dependent cytotoxicity mechanism to kill cancer cells 49 . We hope the industry and academy labs can be equipped with our method to improve the activity of the emerging types of antibody therapeutics.…”

Section: Discussionmentioning

confidence: 99%

A general Fc engineering platform for the next generation of antibody therapeutics

Chen

Zhao

et al. 2021

Theranostics

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Not all therapeutic antibody isotypes are equal: the case of IgM versus IgG in Pertuzumab and Trastuzumab

Abstract: The IgM antibody isotype of Pertuzumab affords simultaneous binding to antigens, but similar binding in Trastuzumab is hindered by steric clashes.

Cited by 29 publications

References 62 publications

Sagacity in antibody humanization for therapeutics, diagnostics and research purposes: considerations of antibody elements and their roles

Sagacity in antibody humanization for therapeutics, diagnostics and research purposes: considerations of antibody elements and their roles

Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective

A general Fc engineering platform for the next generation of antibody therapeutics

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