American Association for Cancer Research 2021: Dual-specific antibodies that bind to BCMA and TACI (HMBD-009) enable better targeting of multiple myeloma in pre-clinical models
Fabien M. Decaillot, Dipti Thakkar, Siyu Guan, Konrad Paszkiewicz, Piers J. Ingram, Jerome D. Boyd-Kikurp. Hummingbird Bioscience, Singapore, Singapore, Hummingbird Bioscience, Houston, TX
F.M. Decaillot: ; Hummingbird Bioscience. D. Thakkar: ; Hummingbird Bioscience. S. Guan: ; Hummingbird Bioscience. K. Paszkiewicz: ; Hummingbird Bioscience. P.J. Ingram: ; Hummingbird Bioscience. J.D. Boyd-Kikurp: ; Hummingbird Bioscience.
Existing immunotherapies for multiple myelomas (MM), including bispecific antibodies, antibody-drug conjugates and chimeric antigen receptor-based strategies, have targeted the B-cell maturation antigen (BCMA) that is expressed at the surface of malignant plasma cells (PCs). Although promising, clinical outcomes are hampered by resistance mechanisms that include BCMA extracellular domain shedding and cell-surface downregulation. In addition, BCMA expression is known to be variable among MM patients. Transmembrane activator and CAML interactor (TACI), another member of the tumor necrosis factor receptor (TNFR) super family, represents another viable drug target. TACI expression largely overlaps with BCMA and expression is also increased in PCs of MM patients. Interestingly, TACI may have a role in maintaining an immunosuppressive tumor microenvironment as its expression was observed to be upregulated in Tregs in MM patient’s tumor load. Activation of TACI in Tregs triggers their proliferation and survival further supporting a pro-tumoral role for this receptor. Altogether, the dual targeting of both BCMA and TACI should be beneficial to the efficient removal of malignant PCs. Despite low sequence homology, BCMA and TACI share a similar 3D structure, which is likely the reason that APRIL (A proliferation-Inducing ligand) binds to both receptors. We applied our proprietary Rational Antibody Discovery platform to successfully direct the generation of mouse IgG clones able to bind a conserved epitope on BCMA and TACI with sub-nanomolar affinities. In addition, these antibodies were able to inhibit the binding of BCMA to APRIL – an interaction known to favor MM tumor growth and survival. Two IgG clones were successfully humanized and retained their capacity to bind to both BCMA and TACI when heterologously expressed on HEK293, or endogenously expressed in MM cancer cell lines such as H929. No cross-reactivity to other TNFR family members was observed. In antibody-dependent cell-mediated cytotoxicity (ADCC) assays, these clones were able to induce efficient cell killing by binding either BCMA or TACI. Moreover, our lead dual-specific anti-BCMA/anti-TACI antibody (HMBD-009) showed better tumor control compared to other anti-BCMA only antibodies in pre-clinical tumor models of MM. Dual-specific antibodies able to efficiently target both BCMA and TACI represent a promising new avenue to improve the elimination of malignant PCs from MM patients.