mAbs
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Nerve growth factor (NGF) is indispensable during normal embryonic development and critical for the amplification of pain signals in adults. Intervention in NGF signaling holds promise for the alleviation of pain resulting from human diseases such as osteoarthritis, cancer and chronic lower back disorders. ⋯ Functional and structural comparisons between tanezumab and the mouse 911 precursor antibody using neurotrophin-specific cell survival assays and X-ray crystal structures of both Fab-antigen complexes illustrated high fidelity retention of the NGF epitope. These results suggest the potential for wide applicability of the LSM method for optimization of well-characterized antibodies during humanization.
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Calcitonin gene-related peptide (CGRP) is a well-validated target for migraine therapy and a known potent systemic vasodilator. LBR-101 is a monoclonal antibody against CGRP in clinical development for the preventive treatment of episodic and chronic migraine. Understanding the hemodynamic and cardiovascular consequences of chronic CGRP inhibition is therefore warranted. ⋯ To this end, two independent studies were conducted in monkeys: a single dedicated cardiovascular safety study and a repeat-dose, chronic study, both with electrocardiogram and hemodynamic assessments. LBR-101 was very well tolerated in both studies, with no clinically significant changes noted in any hemodynamic parameter, nor any relevant changes noted in any ECG parameter. In cynomolgus monkeys, cardiovascular and hemodynamic parameters do not appear to be affected by long-term inhibition of CGRP with LBR-101.