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Jeffrey, S.C. et al.

Scott C. Jeffrey, Minh T. Nguyen, Ruth F. Moser, Damon L. Meyer, Jamie B. Miyamoto, Peter D. Senter,

Minor groove binder antibody conjugates employing a water soluble beta-glucuronide linker.

The minor groove binder beta-glucuronide drug-linker 3 was constructed from amino CBI 1 and determined to be a substrate for Escherichia coli beta-glucuronidase (EC 3.2.1.31), resulting in facile drug release. Compound 3 was conjugated to mAbs cAC10 (anti-CD30) and h1F6 (anti-CD70) to give antibody-drug conjugates (ADCs) with potencies comparable to that of free drug 1. The ADCs were largely monomeric at intermediate loading levels (4-5drug/mAb), in contrast to highly aggregated p-aminobenzylcarbamate dipeptide-based ADCs of 1 previously reported. Significant levels of immunologic specificity were observed with cAC10-3 by comparing antigen positive versus negative cell lines and binding versus non-binding control ADCs. The water soluble beta-glucuronide linker is stable in plasma and effectively delivers drugs to target cells leading to potent cytotoxic activities.[1]

References

Minor groove binder antibody conjugates employing a water soluble beta-glucuronide linker. Jeffrey, S.C., Nguyen, M.T., Moser, R.F., Meyer, D.L., Miyamoto, J.B., Senter, P.D. Bioorg. Med. Chem. Lett. (2007) [Pubmed]

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