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Significance Conventional antibodies often fail to bind small molecule targets with sufficiently high affinity and specificity. To address this need, we have developed a Kappa-on-Heavy (KoH) mouse which produces antibody-like molecules with fully human light-chain variable dimers termed KoH bodies. For MBG and nicotine, KoH mice produce more clonotypes of antigen-specific antibodies than mice expressing a conventional IgG format. Selected MBG-specific KoH bodies have biophysical properties similar to conventional antibodies but bind MBG with higher affinity. Crystallographic analysis of MBG bound to a KoH Fab reveals that the light-chain variable dimer has a deeper binding pocket than a conventional Fab. Thus, KoH bodies have a unique binding interface, enabling them to bind small molecules with higher efficiency than conventional antibodies.

Kappa-on-Heavy (KoH) bodies are a distinct class of fully-human antibody-like therapeutic agents with antigen-binding properties