RO7204239, GYM329, RG6237 Clinical Naked monospecific

We generated an antibody that binds specifically to the latent form of myostatin, blocking its activation. We engineered it with a recently developed antibody engineering technology–the sweeping technology–which results in the very effective elimination of the specific antigen from circulation by forcing the internalization of antibody-antigen complex into cells. The effect of the latent myostatin-sweeping antibodies in increasing muscle strength and mass was tested in a muscle atrophy and muscular dystrophy mouse models. Our results showed that, by eliminating the myostatin from both skeletal muscle and from plasma, this novel and potent antibody greatly increased muscle strength and mass at about 10-fold lower doses compared to other mature myostatin antibodies or non-sweeping latent myostatin antibodies. We selected the final candidate for clinical development among them, and called it GYM329/RG6237. https://doi.org/10.1016/j.nmd.2019.06.185 Anti-latent myostatin antibodies were generated in rabbits by alternatively immunizing the animals with recombinant human and mouse latent myostatin to enrich cross-reactive clones. Screening of B cell supernatants from the immunized rabbits through a binding assay identifed clones that specifcally bind the latent and not the mature myostatin. Tey were then functionally screened through the Smad3/4-binding elements-driven secreted alkaline phosphatase (SEAP) reporter gene assay. We assessed the candidate antibodies’ inhibitory activity against BMP1-mediated activation of myostatin, and MST1032 was fnally selected as the lead antibody based on its strong activity. The variable domain of MST1032 was humanized and engineered to confer pH-dependent binding essential for the sweeping function through a comprehensive mutagenesis method described elsewhere41. For the Fc region, human IgG1 was chosen as template and was engineered for selective and enhanced binding to the human FcγRIIb and for stronger afnity to FcRn in acidic pH conditions. Te resulting antibody was named GYM329. ACT-Fc is also applied to crovalimab, AMY109 and GYM329 (engineered (M428L/N434A) to have enhanced affinity to FcRn at an acidic pH to extend the plasma half-life of the antibody)