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

• Published in: mAbs 2024, Vol.16 (1), p.2310248-2310248
• Main Authors: Zhu, Dan, Hadjivassiliou, Haralambos, Jennings, Catherine, Mikolon, David, Ammirante, Massimo, Acharya, Sharmistha, Lloyd, Jon, Abbasian, Mahan, Narla, Rama Krishna, Piccotti, Joseph R, Stamp, Katie, Cho, Ho, Hariharan, Kandasamy
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bispecific; CD20; CD47; CD47 Antigen; detune; Immunoglobulin G - therapeutic use; Immunotherapy; Lymphoma, Non-Hodgkin; Neoplasms - drug therapy; non-Hodgkin’s lymphoma; Phagocytosis
• ISSN: 1942-0862; 1942-0870
• DOI: 10.1080/19420862.2024.2310248

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.