The Immune Response to Therapeutic Antibodies

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Background

Therapeutic antibodies have revolutionized the treatment of numerous serious diseases in particular chronic diseases with a complex physiopathology such as cancer, autoimmune, and inflammatory disorders. Therapeutic antibodies are also used to treat acute diseases such as COVID-19. Although, the use of therapeutic antibodies has led to considerable progress in the treatment of numerous diseases, such therapies are often associated with adverse events and loss of the therapeutic response due in part to an undesired immune response to the therapeutic agent.

Although the progressive humanization of therapeutic antibodies from mouse antibodies to chimeric, humanized, and finally to fully human antibodies, has considerably reduced immunogenicity, even fully human monoclonal antibodies can elicit an immune response characterized by the generation of anti-idiotypic alloantibodies due to a lack of central tolerance to the CDR region of the antibody.

Even though the activity of therapeutic antibodies is mediated principally by the CDR region, engagement of the Fc moiety with components of the cellular immune system can mediate ADCC, ADCP, and CDC activity which constitutes an important part of the activity of some therapeutic antibodies.

Different protein engineering strategies have given rise to both bispecific, and tri-specific therapeutic antibodies such as T-cell engaging-bispecific antibodies that engage CD3 together with, for example, the B-lymphocyte antigen CD19.

Bi-specific antibodies exist in numerous formats ranging from two linked antigen binding domains to full-length IgG-like molecules with additional domains, all of which are potentially immunogenic. Immunogenicity risk assessment and mitigation of the immune response to treatment with therapeutic antibodies is a central theme of this collection which will include articles on sequence-based protein engineering strategies designed to improve therapeutic activity while mitigating immunogenicity and the absence of tolerance.

The objective of this new Research Topic is then to constitute a collection of original research articles and reviews that together provide a comprehensive and up-to-date perspective of the principal aspects of the immunogenicity of therapeutic antibodies.

We also expect submissions based on (but not limited to):

- The role of the innate immune response, including the activation of complement, as well as the humoral response leading to the formation of anti-drug antibodies (ADA), that can alter the pharmacokinetics and lead to the formation of immunocomplexes that can impact efficacy and safety.

- The formation of neutralizing antibodies (NABs) and the cellular immune response against therapeutic antibodies are also important themes of the collection as are methods to quantify ADAs and NAbs using appropriate validated assays and statistical procedures to interpret results within the guidelines of the regulatory authorities.

- Immunogenicity risk assessment is a complex problem that is influenced by numerous drug and process-related factors, as well as patient, and treatment-related factors, and constitutes an important part of this topic.

- An underappreciated, non-sequence risk of immunogenicity includes direct mechanism of action (MOA) of the therapeutic and target liability, including membrane-bound and soluble forms. Manuscripts that highlight this risk, and potential methods to assess this risk, will be considered favorably for inclusion in this Research Topic.

- Pre-existing serum reactivity to engineered antibody constructs can pose an immunogenicity risk. Assays to detect the presence of pre-formed, cross-reactive serum antibodies to novel B cell neo-epitopes present in engineered therapeutics such as bi-and tri-specific antibodies can inform on potential safety risks and the development of treatment-emergent ADAs upon administration of the therapeutic antibody. Manuscripts describing advances in the detection and prediction of the clinical impact of these pre-ADAs will be considered favorably for inclusion in this collection.

- Papers describing predictive in silico models based on machine learning using in vitro data obtained from for example the identification of T-cell epitopes from predicted peptide binding to MHC class II molecules, and MHC-associated proteomics, as well as T cell activation assays, are becoming increasingly important and can be used as the basis to re-engineer antibodies to eliminate predicted T-cell epitopes and reduce immunogenicity. Manuscripts that contribute to knowledge in this area will be considered for inclusion in this collection.

Topic Editor Dr. Michael Tovey​​​​ is MD of Svar France which develops reporter-gene cell lines that could be used to detect neutralizing antibodies against therapeutic agents. Dr. Arno Kromminga is also affiliated with BioNTech which works in the field of therapeutic antibodies; The other Topic Editors declare no competing interests with regard to the Research Topic subject

Keywords: Therapeutic antibodies, CDR region, bispecific antibodies, neutralizing antibodies, IRA, predictive models, MHC class II, anti-drug antibodies (ADA)

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