A bispecific CD47/CD19 antibody harnesses the phagocytic potential of tumor-associated macrophages (TAMs) and remodels the tumor microenvironment to effectively control B-cell lymphoma growth in mice
Xavier Chauchet, Laura Cons, Laurence Chatel, Leticia Barba, Eric Hatterer, Vanessa Buatois, Limin Shang, Krzysztof Masternak, Zoë Johnson, Nicolas Fischer, Marie Kosco-Vilbois, Walter Ferlin
Novimmune S.A., Geneva, Switzerland
The “don’t eat me” signal, CD47, which inhibits phagocytosis, is commonly overexpressed in many cancers and promotes immune evasion. Although tumor-associated macrophages (TAMs) are often considered pro-tumorigenic, several studies report increased phagocytic potential and tumoricidal function in the presence of antibodies (Ab). Therefore, targeting the CD47-SIRPα axis is an attractive approach to potentially harness phagocytes for tumor control. A bispecific antibody (BiAb) was generated that binds CD47 and CD19 in order to selectively interfere with CD47/SIRPα on CD19+ B cells. In addition to in vitro data demonstrating that the BiAb effectively kills CD19+ human tumor B cells through ADCP and ADCC (antibody-dependent cellular phagocytosis or cytotoxicity), we have observed significant tumor suppression in vivo, either as a monotherapy or in combination therapy. The BiAb controlled human lymphoma cell growth when sub-cutaneously implanted into NOD scid mice, in a manner dependent on the co-ligation of both CD19 and CD47. Moreover, a combination of the BiAb and an anti-CD20 mAb was shown to act synergistically to control tumor growth, leading even to tumor regression. Examination of the tumors revealed that: 1) TAMs represent the major murine infiltrating cell subtype (i.e., 60% of murine leukocytes); 2) BiAb treatment enhances the tumoricidal activity of macrophages (i.e., more macrophages engulfing tumor cells) and 3) the BiAb reshapes the tumor microenvironment by promoting an antitumor M1-like phenotype and reducing the proportion of CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs). These data demonstrate that the CD47/CD19 BiAb approach delivers an effective way to harness the phagocytic potential of TAMs.