Developability Improvement of an MMP-9 Inhibitory mAb by CDR-H3 Hydrophobic Residue Substitution

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ID: 326296
2026
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Abstract
Abstract Background Besides required biochemical and biological functions, suitable biophysical characteristics or developability are critical for the success of mAb therapeutics. Aiming to develop disease-modifying therapeutics for diabetic peripheral neuropathy (DPN), this study applied protein engineering strategies to improve the developability of an MMP-9 inhibitory mAb. Methods A miniature diversity was introduced to replace two hydrophobic residues in CDR-H3. Following mAb production, comprehensive panels of biochemical and biophysical properties were measured. The optimized mutant was further validated by pharmacokinetics and in vivo efficacy studies. Results The optimized mutant exhibited favorable developability properties while retaining its biochemical activities, including high production yield, colloidal stability, nanomolar binding affinity and inhibition potency, exclusive selectivity, no non-specific binding, proteolytic resistance, cross-species activity, and thermostability. Furthermore, the optimized mAb demonstrated remarkably improved pharmacokinetics and significantly prolonged therapeutic effects in a mouse model of DPN. Conclusions Given the critical role of developability in mAb therapeutics, this study highlights a practical strategy for improving both developability and in vivo efficacy through rational site-directed mutagenesis.
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Authors Sushma Krishnan, L.B. Ma, Wei He, Weiyuan Hu, Ki Baek Lee, Qin Zhang, Ru‐Rong Ji, Xinli Liu, Xin Ge
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Journal Antibody Therapeutics
Year 2026
DOI
10.1093/abt/tbag044
URL
https://doi.org/10.1093/abt/tbag044
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