Myeloid cell-mediated killing of B-ALL by CD38 and CD20 IgA antibody variants is enhanced by CD47/SIRPα interference.

Enhancing myeloid effector cell recruitment may improve immunotherapy by monoclonal antibodies, including those against acute lymphoblastic leukemia (ALL). To assess the expression of target antigens in B-cell ALL (B-ALL), we compared mRNA profiling of 559 patient leukemia samples across 18 molecular subtypes with that of representative cell lines. The latter served as target cells to compare human immunoglobulin G1 (IgG1) or IgA2 variants against CD19, CD20, or CD38 in antibody-dependent cellular phagocytosis (ADCP) by macrophages and antibody-dependent cell-mediated cytotoxicity (ADCC) by polymorphonuclear leukocytes (PMN). Interestingly, antibodies against broadly expressed CD19 were negligibly effective in mediating ADCP or ADCC. Antibodies against CD20 or CD38, the former variably expressed across subtypes, triggered ADCP by macrophages both as IgG1 and IgA2. However, PMN-mediated ADCC against CD20 or CD38 was only observed with IgA2 variants but not with respective IgG1 antibodies. Blocking the myeloid checkpoint CD47/signal regulatory protein α (SIRPα) enhanced ADCP and ADCC by IgA2 antibodies against CD20 and CD38 but not CD19. Both CD47 and its enzymatic modifier glutaminyl-peptide cyclotransferase-like protein (QPCTL), which can be inhibited by small molecules, were broadly expressed across B-ALL subtypes. QPCTL catalyzes the formation of an N-terminal pyroglutamic acid on CD47, which is directly involved in CD47/SIRPα interactions as shown by novel engineered CD47 variants. Importantly, the combination of anti-CD38 IgA2 and CD47 blockade was effective against xenografted B-ALL in human FcαRI (CD89) transgenic NXG mice. Together, these studies support combining anti-CD38 IgA2 with CD47 interference to improve myeloid effector cell recruitment for B-ALL immunotherapy.