Abstract
The sole inhibitory Fcγ receptor CD32b (FcγRIIb) is expressed throughout B and plasma cell development and on their malignant counterparts. CD32b expression on malignant B cells is known to provide a mechanism of resistance to rituximab that can be ameliorated with a CD32b-blocking antibody. CD32b, therefore, represents an attractive tumor antigen for targeting with a monoclonal antibody (mAb). To this end, two anti-CD32b mAbs, NVS32b1 and NVS32b2, were developed. Their complementarity-determining regions (CDR) bind the CD32b Fc binding domain with high specificity and affinity while the Fc region is afucosylated to enhance activation of FcγRIIIa on immune effector cells. The NVS32b mAbs selectively target CD32b+ malignant cells and healthy B cells but not myeloid cells. They mediate potent killing of opsonized CD32b+ cells via antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) as well as complement-dependent cytotoxicity (CDC). In addition, NVS32b CDRs block the CD32b Fc-binding domain, thereby minimizing CD32b-mediated resistance to therapeutic mAbs including rituximab, obinutuzumab, and daratumumab. NVS32b mAbs demonstrate robust antitumor activity against CD32b+ xenografts in vivo and immunomodulatory activity including recruitment of macrophages to the tumor and enhancement of dendritic cell maturation in response to immune complexes. Finally, the activity of NVS32b mAbs on CD32b+ primary malignant B and plasma cells was confirmed using samples from patients with B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma. The findings indicate the promising potential of NVS32b mAbs as a single agent or in combination with other mAb therapeutics for patients with CD32b+ malignant cells.
Highlights
Multiple myeloma is a complex disease characterized by the presence of profound intratumoral heterogeneity that increases progressively from the stages of monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic/smoldering multiple myeloma to symptomatic or clinical multiple myeloma
Leveraging the Broad Multiple Myeloma Genetics Portal [12] and the Gene Expression Omnibus repository [13], the inhibitory FcgR CD32b was found to be frequently expressed at the transcript level in malignant cells including multiple myeloma, DLBCL, MCL, CLL, and follicular lymphoma (Fig. 1A)
Consistent with prior reports [3,4,5], CD32b is expressed on the cell surface of B and plasma cells and their malignant counterparts in a significant portion of patients with CLL, non-Hodgkin Lymphoma (NHL), and multiple myeloma
Summary
Multiple myeloma is a complex disease characterized by the presence of profound intratumoral heterogeneity that increases progressively from the stages of monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic/smoldering multiple myeloma to symptomatic or clinical multiple myeloma. Despite the approval of novel mAb medicines targeting CD38 2) as well as small-molecule classes including proteasome inhibitors and thalidomide analogue immunomodulatory drugs, the majority of patients relapse. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). M.J. Meyer is the senior author of this article
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