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CD32b (FcγR2b), the sole inhibitory Fcγ receptor, negatively regulates immune function and is expressed throughout B 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 thereby 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 enabling enhanced activation of FcγR on immune effector cells. This specificity and optimized potency is highlighted in whole blood assays where NVS32b2 depletes CD32b positive B cells but spares immune subsets with low CD32b expression or expression of the homologous CD32a. The antibodies mediate potent killing of opsonized cells via antibody dependent cell-mediated cytotoxicity, antibody dependent cellular phagocytosis, and complement dependent cytotoxicity. Additionally, NVS32b mAbs’ CDR block the CD32b Fc binding domain, thereby minimizing CD32b mediated resistance to therapeutic mAbs with Fc dependent activity including rituximab, obinutuzumab, and daratumumab. In vivo, NVS32b mAbs demonstrate robust antitumor activity against CD32b positive xenografts and immunomodulatory activity including recruitment of intratumoral macrophages. The NVS32b mAbs’ activity against malignant B and plasma cells featuring a range of CD32b expression demonstrates their therapeutic potential, as a single agent or in combination with therapeutics including mAbs with Fc dependent activity. Citation Format: Haihui Lu, Dongshu Chen, Sunyoung Jang, Babette Wolf, Stefan Ewert, Meghan Flaherty, Fangmin Xu, Sinan Isim, Yeonjiu Shim, Christina Dornelas, Nicole Balke, Xavier Charles Leber, Meike Scharenberg, Johanna Koelln, Eugene Choi, Rebecca Ward, Jennifer Johnson, Thomas Calzascia, Isabelle Isnardi, Juliet Williams, Heather Huet, Emma Lees, Matthew J Meyer. Discovery and characterization of next generation monoclonal antibodies targeting the inhibitory Fc gamma receptor CD32b for the treatment of B and plasma cell malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C028. doi:10.1158/1535-7163.TARG-19-C028