SRF231: Enhancing Macrophage Phagocytosis to Combat Hematologic Malignancies

The CD47 molecule, a member of the immunoglobulin superfamily, plays a role in various cellular activities such as cell movement, attachment, and the function of T cells. It is known to interact with SIRPα, an inhibitory protein found on macrophages, which prevents the engulfment of cells that express CD47. Initially identified in ovarian cancer, CD47 is also found in a range of other human tumor types, both blood-related and solid. Elevated levels of CD47 are linked to unfavorable outcomes in blood cancers. While it is present at low levels on most non-cancerous cells, changes in its expression or distribution on the cell surface can indicate aging or damage, particularly in red blood cells.

The high level of CD47 on cancerous cells can impede their clearance by the immune system, hindering antigen presentation and T cell activation, which helps tumors evade immune responses. However, interventions that block the interaction between CD47 and SIRPα can counteract this, improving the effectiveness of therapeutic antibodies that rely on antibody-dependent cellular cytotoxicity (ADCC).

A CD47-blocking antibody, SRF231, was developed and has been shown to have a high affinity for human CD47, disrupting the CD47-SIRPα interaction. This monoclonal antibody facilitates the phagocytic removal of hematologic tumor cells and cell lines by macrophages in vitro. SRF231 has been demonstrated to significantly increase the phagocytosis of certain tumor cell lines, such as Raji, with a preference for tumor cells over normal white blood cells and red blood cells. The phagocytic effect can be further enhanced in the presence of other antibodies that target the tumor cells.

Preclinical studies using murine xenograft models of blood malignancies have shown that SRF231 can significantly inhibit tumor growth, both as a standalone treatment and in combination with other antibodies. In one model, SRF231 as a single agent resulted in substantial tumor growth inhibition. The effectiveness of SRF231 appears to be dependent on macrophages, as their depletion reduced the extent of tumor growth inhibition. Furthermore, SRF231 treatment also influences the number and polarization of tumor-associated macrophages.

In conclusion, the monoclonal antibody SRF231 has shown promise in inducing the clearance of tumor cells in preclinical models of myeloma and lymphoma, both as a monotherapy and in combination with other antibodies. Given these findings, SRF231 is a candidate for further development in the treatment of blood cancers and was anticipated to enter clinical trials in 2017.