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Current Considerations on Characterization of Immune Response to Multi-Domain Biotherapeutics

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Abstract

Compounds containing two or more structural domains with a distinct mode of action relevant to functionality have been defined as multi-domain biotherapeutics (MDBs). Several modalities, including endogenous protein fusions with an antibody Fc fragment or another polypeptide, bispecific antibodies, antibody–drug conjugates, as well as polyethylene glycol conjugates have been viewed as examples of MDBs. Similar to other biotherapeutics, MDBs have the potential to induce a host immune response, commonly detected in the form of anti-drug antibodies (ADAs). The need to characterize ADA specificity to a particular domain of the MDB has been identified as a potential regulatory requirement based on the compound nature of the drug and associated immunogenicity risk factors. MDB-related immunogenicity risk factors are discussed herein. The relative risk level of each of the immunogenicity factors was analyzed based on publicly available information. It is proposed that MDB-related immunogenicity risk factors can be divided into major and minor categories. Major risk category factors include (a) presence of immunogenic structural or linear epitopes of either non-human or human sequence origin and (b) significant homology of an MDB domain to an endogenous protein with a specific and unique function. Proposed minor risk category factors include (a) epitope spread, (b) repetitive antigenic structure of MDB, and (c) hapten-like effect due to chemical conjugation or fusion with a larger protein. Detailed modality-based information on several examples of MDBs is presented to support this proposal.

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Authors and Affiliations

  1. Pfizer Inc., 1 Burtt Rd., Andover, MA, 01810, USA

    Boris Gorovits

  2. Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Kun Peng

  3. Bioagilytix, Lademannbogen 10, 22339, Hamburg, Germany

    Arno Kromminga

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  1. Boris Gorovits
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  2. Kun Peng
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Correspondence to Boris Gorovits.

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No funding was received in preparation of this review.

Conflict of interest

BG is employed by Pfizer Inc., which is involved in development of biotherapeutics of different modalities and indications. KP is employed by Genentech Inc., which is involved in development of biotherapeutics of different modalities and indications. AK is employed by Bioagilytix Inc., which is involved in development of biotherapeutics of different modalities and indications.

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Gorovits, B., Peng, K. & Kromminga, A. Current Considerations on Characterization of Immune Response to Multi-Domain Biotherapeutics. BioDrugs 34, 39–54 (2020). https://doi.org/10.1007/s40259-019-00389-8

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