Deciphering TJC4: A Distinctive Anti-CD47 Antibody with Enhanced Safety and Efficacy

A novel anti-CD47 antibody, TJC4, has been developed to counteract the "do not eat" signal that tumor cells use to evade phagocytosis by macrophages. This antibody is designed to have a reduced impact on normal red blood cells (RBCs) and platelets, addressing the anemia and thrombocytopenia issues associated with other CD47-targeting treatments. Pre-clinical data suggests a favorable safety profile for TJC4.

The antibody was identified through screening a human single chain variable fragment (ScFv) library against the extracellular domain of human CD47. Binders with unique sequences were developed into full antibodies and further tested for their interaction with human RBCs and tumor cells.

Comparative experiments were conducted to assess TJC4's binding to RBCs, hemagglutination, and its ability to block CD47-SIRPa interaction and enhance macrophage-mediated phagocytosis. In vivo tumor models were used to evaluate TJC4's anti-tumor efficacy, both as a monotherapy and in combination with other treatments. Hematological parameters were also analyzed in cynomolgus monkeys following TJC4 administration.

The mechanism behind TJC4's RBC sparing properties was investigated using X-ray crystallography, revealing a unique binding pose and epitope. The influence of CD47 glycosylation on RBCs was also examined.

Results indicate that TJC4, a fully human anti-CD47 IgG4 antibody, has a similar binding affinity to human and cynomolgus monkey CD47. It effectively blocks the CD47-SIRPa interaction, enhancing macrophage phagocytosis of CD47+ tumor cells. TJC4 demonstrated complete tumor eradication in a Raji cell xenograft model and extended survival in an AML model. In combination with Rituximab, TJC4 showed superior efficacy in a DLBCL model.

TJC4 exhibits minimal binding to healthy human RBCs and platelets, with minimal and transient impacts on RBCs in cynomolgus monkeys at the highest tested dose. The unique structural properties of TJC4, including a novel conformational epitope and a potential N-linked glycosylation site, are hypothesized to shield critical epitopes on CD47, preventing binding to human RBCs. This was confirmed by the restoration of TJC4 binding to deglycosylated RBCs.

In conclusion, TJC4 represents a next-generation therapeutic anti-CD47 antibody that maintains anti-tumor efficacy without the hematological side effects, setting it apart from other CD47-targeting agents in clinical development. The disclosures indicate employment and equity ownership by several individuals at I-Mab Biopharma.