Papers of the Week

ALD403 is a genetically engineered, humanized immunoglobulin G1 monoclonal antibody that inhibits the action of human calcitonin gene-related peptide (CGRP). Clinical trial data indicate that ALD403 is effective as a preventive therapy for migraine and has an acceptable safety profile. For preclinical characterization of ALD403, rabbit antibodies targeting α-CGRP were humanized and modified to eliminate Fcγ-receptor (FcγR) and complement interactions. The ability of ALD403 to inhibit CGRP-induced cyclic adenosine monophosphate (cAMP) production was assessed using a cAMP bioassay (Meso Scale Discovery). The IC50 for inhibition of cAMP release was 434 and 288 pM with the rabbit-human chimera antibody and the humanized ALD403, respectively. ALD403 inhibited α-CGRP binding with an IC50 of 4.7 x 10-11 and 1.2 x 10-10 for the α-CGRP and AMY1 receptors, respectively. ALD403 did not induce antibody-dependent cellular cytotoxicity nor complement-dependent cytotoxicity and did not stably interact with any of the FcγR mediating these functions, exhibiting only weak binding to FcγRI. ALD403 significantly lowered capsaicin-induced blood flow responses in rodents at all time points starting at 5 minutes post-application in a dose-dependent manner. In conclusion, ALD403 is a potent functional ligand inhibitor of α-CGRP‒driven pharmacology. SIGNIFICANCE STATEMENT: α-CGRP blockade by ALD403 was assessed via radiolabeled ligand displacement, in vitro inhibition of cell signaling, and in vivo inhibition of capsaicin-induced vasodilation. Lack of engagement of Fc-mediated immune-effector functions by ALD403 was shown.