Abstract 1872: Generation of bispecific and trispecific T cell engagers (TCEs) and NK cell engagers (NKE)s without prior IgG reengineering

Abstract

Abstract T cell and NK cell-redirecting antibodies are emerging as promising modalities in targeted immunotherapy. New technologies are overcoming the limitations of 1st generation immune cell-redirecting bispecifics, especially extending half-life, reducing immunogenicity and improving safety. For example, in the field of T cell engagers (TCEs), a plethora of molecular architectures has entered the clinic, the vast majority generated by genetic engineering of an IgG to bind both a tumor-associated antigen (TAA) and CD3 or 4-1BB. Similarly, recombinant DNA technology enables the C-terminal fusion of a cytokine (e.g. IL-2 or IL-15) to an IgG to obtain NK cell engagers (NKEs). We have shown earlier that the native glycan of a monoclonal antibody provides a privileged site for attachment of cytotoxic payloads,1 providing antibody-drug conjugates (ADCs) with significantly enhanced therapeutic index. This technology, known as GlycoConnect™, has been adapted by various drug developers (e.g. ADC Therapeutics, Mersana Therapeutics and others) and is now applied in two (2) clinical programs as well as multiple late-stage preclinical programs. Here we demonstrate how GlycoConnect™ technology can be applied to generate TCEs or NKEs by selective attachment of scFv (anti-CD3, anti-CD28) or cytokines (IL-15), with concomitant Fc-silencing. Moreover, an existing bispecific TCE (TAA/CD3) can be further boosted by attachment of anti-CD28 scFv for further T cell activation. Molecular architectures can be readily tailored to 2:2 or 2:1 ratio (TAA:scFv or cytokine) to mitigate adverse events like cytokine release syndrome, and even 2:1:1 formats. Structural and functional studies will be presented to corroborate the architecture and biological activity of these GlycoConnect™ bispecifics and trispecifics, in terms of binding, immune cell engagement and cell-killing potential. 1van Geel et al. Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of Native mAbs Provides Homogeneous and Highly Efficacious Antibody−Drug Conjugates. Bioconj. Chem. 2015, 26, 2233-2242. Citation Format: Remon van Geel, Floris van Delft. Generation of bispecific and trispecific T cell engagers (TCEs) and NK cell engagers (NKE)s without prior IgG reengineering [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1872.