Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer.

ABSTRACT: Agonists of the TNF superfamily of receptors hold promise as novel therapy for cancer. Recent data on agonistic anti-murine TNF receptors (TNFR) such as CD40 suggest that the specific engagement of Fc-receptor (FcR) is required for optimal antitumor effects, prompting calls to engineer anti-human CD40 and other TNFR mAb accordingly. CP-870,893 is a fully human anti-CD40 mAb, selected in part because it is an IgG2 which is presumed to have poor reactivity with FcR; however, CP-870,893 has been evaluated in multiple clinical trials with beneficial activity in patients with melanoma, pancreatic and other cancers. Here, we confirmed that the activity of anti-murine CD40 mAb was dependent on Fc?RIIB engagement, was decreased significantly in Fc?RIIB (-/-) mice, and upon Fc-crosslinking anti-mouse CD40 mAb enhanced the activation of antigen presenting cells. In contrast, the CP-870,893-mediated activation of human B cells was not enhanced with anti-IgG-crosslinking nor abrogated when used as an F(ab)'2 reagent. Crosslinking of CP-870,893 using the CD32-expressing K562 cells yielded an Fc-dependent modest increase in the expression of some activation markers relative to that of the soluble CP-870,893 mAb. Classic Fc-dependent functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) were minimal for CP-870,893 as compared to the IgG1 anti-CD20 mAb rituximab, which mediated both ADCC and CMC in parallel assays. Anti-mouse CD40 mAb competed for the CD40 ligand binding site, but CP-870,893 did not. Thus, Fc-crosslinking is not an essential requirement for agonistic anti-human CD40 mAb, whose potency is more dependent on the CD40 epitope recognized and the strength of the signal achieved.

SUBMITTER: Richman LP 

PROVIDER: S-EPMC3883444 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature