Bispecific small molecule-antibody conjugate targeting prostate cancer

We have developed a semisynthetic method for the production of bispecific antibody-like therapeutics consisting of a small molecule targeting moiety conjugated to an antibody. A highly selective prostate-specific membrane antigen-binding ligand was site specifically conjugated to a mutant α cluster of differentiation 3 (αCD3) Fab containing an unnatural amino acid with orthogonal chemical reactivity. The optimized conjugate showed potent in vitro activity, good serum half-life, and potent in vivo activity in prostate cancer xenograft mouse models. This semisynthetic approach is likely to be applicable to the generation of additional bispecific agents using drug-like ligands selective for other cell-surface receptors.