Key result
A newly developed immunoassay accurately quantitates serum latent myostatin, which increases and reaches a dose-dependent plateau approximately 20 days after SRK-015 treatment in cynomolgus monkeys.
Why the study?
Quantitation of latent myostatin in serum may serve as a biomarker for target engagement of SRK-015, but an accurate, drug-tolerant assay was needed.
A sensitive plate-based electrochemiluminescent immunoassay was developed to accurately quantitate latent myostatin in serum samples, serving as a biomarker for SRK-015 target engagement.
SRK-015 selectively inhibits myostatin activation in animals; leaves open clinical translation for muscle wasting disorders.
Myostatin, a member of the transforming growth factor β (TGFβ) superfamily, is a key regulator of skeletal muscle mass and a therapeutic target for muscle wasting diseases. We developed a human monoclonal antibody, SRK-015, that selectively binds to and inhibits proteolytic processing of myostatin precursors, thereby preventing growth factor release from the latent complex. As a consequence of antibody binding, latent myostatin accumulates in the circulation of animals treated with SRK-015 or closely related antibodies, suggesting that quantitation of latent myostatin in serum may serve as a biomarker for target engagement. To accurately measure SRK-015 target engagement, we developed a sensitive plate-based electrochemiluminescent immunoassay to quantitate latent myostatin in serum samples. The assay selectively recognizes latent myostatin without cross-reactivity to promyostatin, mature myostatin, or closely related members of the TGFβ superfamily. To enable use of the assay in samples from animals dosed with SRK-015, we incorporated a low-pH step that dissociates SRK-015 from latent myostatin, improving drug tolerance of the assay. The assay meets inter- and intra-assay accuracy and precision acceptance criteria, and it has a lower limit of quantitation (LLOQ) of 10 ng/mL. We then tested serum samples from a pharmacology study in cynomolgus monkeys treated with SRK-015. Serum latent myostatin increases after treatment with SRK-015, reaches a dose-dependent plateau approximately 20 days after dosing, and trends back toward baseline after cessation of antibody dosing. Taken together, these data suggest that this assay can be used to accurately measure levels of the primary circulating form of myostatin in population-based or pharmacodynamic studies.
No takes yet. Share an insight, caveat, or question.
Cote et al. (2019) studied this question. SRK-015 was evaluated on Serum latent myostatin levels. A newly developed immunoassay accurately quantitates serum latent myostatin, which increases and reaches a dose-dependent plateau approximately 20 days after SRK-015 treatment in cynomolgus monkeys.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: