CC-96673 (BMS-986358), an affinity-tuned anti-CD47 and CD20 bispecific antibody with fully functional fc, selectively targets and depletes non-Hodgkin’s lymphoma

ABSTRACT

Cluster of differentiation 47 (CD47) is a transmembrane protein highly expressed in tumor cells that interacts with signal regulatory protein alpha (SIRPα) and triggers a “don’t eat me” signal to the macrophage, inhibiting phagocytosis and enabling tumor escape from immunosurveillance. The CD47-SIRPα axis has become an important target for cancer immunotherapy. To date, the advancement of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hematologic toxicity including anemia. To overcome those challenges a bispecific approach was taken. CC-96673, a humanized IgG1 bispecific antibody co-targeting CD47 and CD20, is designed to bind CD20 with high affinity and CD47 with optimally lowered affinity. As a result of the detuned CD47 affinity, CC-96673 selectively binds to CD20-expressing cells, blocking the interaction of CD47 with SIRPα. This increased selectivity of CC-96673 over monospecific anti-CD47 approaches allows for the use of wild-type IgG1 Fc, which engages activating crystallizable fragment gamma receptors (FcγRs) to fully potentiate macrophages to engulf and destroy CD20⁺ cells, while sparing CD47⁺CD20⁻ normal cells. The combined targeting of anti-CD20 and anti-CD47 results in enhanced anti- tumor activity compared to anti-CD20 targeting antibodies alone. Furthermore, preclinical studies have demonstrated that CC-96673 exhibits acceptable pharmacokinetic properties with a favorable toxicity profile in non-human primates. Collectively, these findings define CC-96673 as a promising CD47 × CD20 bispecific antibody that selectively destroys CD20⁺ cancer cells via enhanced phagocytosis and other effector functions.

KEYWORDS:

• CD20
• CD47
• detune
• non-Hodgkin’s lymphoma
• phagocytosis

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Correction

Abbreviations

ADCC	=	antibody-dependent cellular cytotoxicity
ADCP	=	antibody-dependent cellular phagocytosis
CD	=	cluster of differentiation
CDC	=	complement-dependent cytotoxicity
FcγR	=	fragment crystallizable gamma receptor
IgG	=	immunoglobulin G
SIRPα	=	signal-regulatory protein alpha
VH	=	immunoglobulin heavy chain variable region
VL	=	immunoglobulin light chain variable region

Acknowledgments

The authors thank other team members from Celgene Corporation, including Jeonghoon Sun, Jeffrey Johnson, Henry Chan, Chaity Chaudhury, and Roberto Guzman, for their contributions to the strategy and execution of the experiments.

Disclosure statement

DZ, HH, RK, SA, AM, DM, CJ, KS, and KH are currently, and JL, JP, and HC were previously employees of Bristol Myers Squibb.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19420862.2024.2310248

Correction Statement^&

Current address: Samsung Bioepis, Incheon, South Korea.This article was originally published with errors, which have now been corrected in the online version. Please see Correction (http://dx.doi.org/10.1080/19420862.2024.2354626)

Additional information

Funding

The author(s) reported that there is no funding associated with the work featured in this article.