Engineering hydrophobicity and manufacturability for optimized biparatopic antibody-drug conjugates targeting c-MET.

ABSTRACT: Optimal combinations of paratopes assembled into a biparatopic antibody have the capacity to mediate high-grade target cross-linking on cell membranes, leading to degradation of the target, as well as antibody and payload delivery in the case of an antibody-drug conjugate (ADC). In the work presented here, molecular docking suggested a suitable paratope combination targeting c-MET, but hydrophobic patches in essential binding regions of one moiety necessitated engineering. In addition to rational design of HCDR2 and HCDR3 mutations, site-specific spiking libraries were generated and screened in yeast and mammalian surface display approaches. Comparative analyses revealed similar positions amendable for hydrophobicity reduction, with a broad combinatorial diversity obtained from library out

SUBMITTER: Evers A 

PROVIDER: S-EPMC10793681 | biostudies-literature | 2024 Jan-Dec

REPOSITORIES: biostudies-literature