Lu, Haihui, Molony, Ryan, Chen, Dongshu, Jang, Sunyoung, Wolf, Babette, Ewert, Stefan, Meghan , Flaherty, Xu, Fangmin, Isim, Sinan, Shim, Yeonju, Dornelas, Christina, Balke, Nicole, Leber, Xavier Charles, Scharenberg, Meike, Koelln, Johanna, Choi, Eugene, Ward, Rebecca, Johnson, Jennifer, Calzascia, Thomas, Isnardi, Isabelle, Williams, Juliet, Van de Donk, Niels, Mutis, Tuna, Huet, Heather, Lees, Emma and Meyer, Matthew (2020) Development of anti-CD32b antibodies with enhanced Fc function for the treatment of B and plasma cell malignancies. Molecular cancer therapeutics, 19 (10). pp. 2089-2104. ISSN 1538-8514

Abstract

The sole inhibitory Fcγ receptor CD32b (FcγR2b) is expressed throughout B and plasma cell development and on their malignant counterparts with the highest expression found on multiple myeloma. Additionally, CD32b expression on tumor cells is known to sequester IgG Fc whereby providing a mechanism of resistance to therapeutic monoclonal antibodies (mAb) with Fc dependent activity. Taken together, CD32b represents an attractive tumor antigen for targeting with a mAb. To this end, two anti-CD32b mAbs, NVS32b1 and NVS32b2, were developed. The complementarity-determining regions (CDRs) of these antibodies bind the CD32b Fc binding domain with high specificity and affinity while the Fc region is afucosylated to enhance activation of FcR on immune effector cells. NVS32b mAbs selectively depletes CD32b+ healthy and malignant B cells but spares myeloid cells and CD32a+ cells. These antibodies mediate potent killing of opsonized cells via antibody dependent cellular cytotoxicity and phagocytosis (ADCC & ADCP), as well as complement dependent cytotoxicity (CDC). Additionally, NVS32b CDRs block the CD32b Fc binding domain, thereby minimizing CD32b mediated resistance to therapeutic mAbs with Fc dependent activity, including rituximab, obinutuzumab, and daratumumab. NVS32b mAbs demonstrate robust antitumor activity against CD32b positive xenografts in vivo and immunomodulatory activity including recruitment of macrophages to the tumor microenvironment and enhancement of DC maturation in response to immune-complexes. The activity of NVS32b mAbs on CD32b+ primary malignant B and plasma cells was confirmed on samples from CLL and MM patients. NVS32b mAbs demonstrated great therapeutic potential, as a single agent or in combination with other mAb therapeutics.

Item Type:	Article
Date Deposited:	03 Nov 2020 00:45
Last Modified:	03 Nov 2020 00:45
URI:	https://oak.novartis.com/id/eprint/43572