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Immunogenicity risk assessment and mitigation for engineered antibody and protein therapeutics

Nature Reviews Drug Discovery volume 23, pages 898–913 (2024)Cite this article

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Abstract

Remarkable progress has been made in recent decades in engineering antibodies and other protein therapeutics, including enhancements to existing functions as well as the advent of novel molecules that confer biological activities previously unknown in nature. These protein therapeutics have brought major benefits to patients across multiple areas of medicine. One major ongoing challenge is that protein therapeutics can elicit unwanted immune responses (immunogenicity) in treated patients, including the generation of anti-drug antibodies. In rare and unpredictable cases, anti-drug antibodies can seriously compromise therapeutic safety and/or efficacy. Systematic deconvolution of this immunogenicity problem is confounded by the complexity of its many contributing factors and the inherent limitations of available experimental and computational methods. Nevertheless, continued progress with the assessment and mitigation of immunogenicity risk at the preclinical stage has the potential to reduce the incidence and severity of clinical immunogenicity events. This Review focuses on identifying key unsolved anti-drug antibody-related challenges and offers some pragmatic approaches towards addressing them. Examples are drawn mainly from antibodies, given that the majority of available clinical data are from this class of protein therapeutics. Plausible and seemingly tractable solutions are in sight for some immunogenicity problems, whereas other challenges will likely require completely new approaches.

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Fig. 1: Immune system interactions involved in ADA generation with experimental methods of assessment.
Fig. 2: Overview of immunogenicity risk assessment and mitigation.
Fig. 3: MHC-II are heterodimeric, highly polymorphic peptide-binding proteins.

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Acknowledgements

We thank the following Genentech colleagues for their critical feedback of this article: M. Balazs, S. Cohen, J. Koerber, J. Lill, K. Peng, O. Saad, C. Spiess, S. Swanson, W.-T. Tsai and P. Wu.

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Authors and Affiliations

  1. Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA

    Paul J. Carter

  2. Department of BioAnalytical Sciences, Genentech, Inc., South San Francisco, CA, USA

    Valerie Quarmby

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  1. Paul J. Carter
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  2. Valerie Quarmby
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P.J.C. and V.Q. researched data for this article and wrote it.

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Correspondence to Paul J. Carter or Valerie Quarmby.

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Competing interests

The authors are current (P.J.C.) or former (V.Q.) employees of Genentech, Inc., which develops and commercializes therapeutics, including antibodies and other proteins.

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Related links

IPD-IMGT/HLA database: https://www.ebi.ac.uk/ipd/imgt/hla/about/statistics/

Glossary

Antigen

Any molecule that can bind specifically to an antibody and/or generate peptide fragments that bind to a major histocompatibility complex molecule and are specifically recognized by a T cell receptor.

B cell epitopes

Linear or conformational parts of an antigen that bind to an antibody.

Critical quality attribute

(CQA). A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality.

Deimmunization

Modification of protein sequence to remove B cell and/or T cell epitopes.

Developability

Broad set of desirable drug-like properties of protein therapeutics that includes feasibility of manufacture, stability during storage, ease of administration and favourable pharmacological behaviour in patients, and excludes target binding.

Epitope spreading

Diversification of the B and T cell epitopes recognized by the immune system.

Poly-reactivity

Ability of an antibody to bind multiple self and/or foreign antigens that are unrelated to the cognate antigen(s).

Product-related variants

Truncated and other modified forms, aggregates, precursors, and degradation products arising during manufacturing and/or storage.

Replacement protein therapeutic

Protein therapeutic that is intended to substitute or augment the deficiency of a specific endogenous protein.

Target candidate profile

Set of desired biochemical, biological and biophysical attributes for therapeutic candidates.

T cell epitopes

Peptides that are derived from an antigen that binds to a major histocompatibility complex molecule and are then recognized by cognate T cell receptors.

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Carter, P.J., Quarmby, V. Immunogenicity risk assessment and mitigation for engineered antibody and protein therapeutics. Nat Rev Drug Discov 23, 898–913 (2024). https://doi.org/10.1038/s41573-024-01051-x

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