A novel, blocking, Fc-silent anti-CD40 monoclonal antibody prolongs nonhuman primate renal allograft survival in the absence of B cell depletion.

CD40-CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti-CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti-CD40 antibody can still promote graft survival. The parent anti-CD40 monoclonal antibody HCD122 prolonged allograft survival in MHC-mismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc-silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98-100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was well-tolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection.

Characterization of macrophage subpopulations in colon cancer using tissue microarrays.

AIMS: To determine the pattern of macrophage infiltration in colon cancers and its correlation with clinicopathological characteristics. METHODS AND RESULTS: Colon cancers from 100 patients were arrayed into a tissue microarray (TMA). Four cores per tumour were taken: three from the invasion front (IF) and one from the tumour surface (TS). Macrophages were quantified by immunohistochemistry with antibodies to the PG-M1, KP-1, MRP8, MRP14 and MRP8/14 antigens. The number of macrophages was significantly higher in the TS cores than in the IF cores and both tumour sites showed a higher number of macrophages than the normal mucosa. The number of macrophages decreased in higher stage tumours. The different tumour-associated macrophage (TAM) subpopulations were positively correlated with each other. CONCLUSIONS: The increased number of macrophages in cancers compared with normal colon mucosa indicates that macrophages are attracted to the tumour site. However, decreasing macrophages in higher stage colon cancers suggest that this attraction decreases with tumour progression.