Improving the Therapeutic Index in Cancer Therapy by Using Antibody-Drug Conjugates Designed with a Moderately-Cytotoxic Drug.

Molecular pharmaceutics

PubMedID: 25402018

Govindan SV, Cardillo TM, Rossi EA, Trisal P, McBride WJ, Sharkey RM, Goldenberg DM. Improving the Therapeutic Index in Cancer Therapy by Using Antibody-Drug Conjugates Designed with a Moderately-Cytotoxic Drug. Mol Pharm. 2014;.
The antibody-drug conjugate (ADC), IMMU-130, of the moderately-cytotoxic topoisomerase I inhibitor, SN-38, and the CEACAM5-targeted humanized antibody (MAb), labetuzumab, was evaluated in model systems of human colon carcinoma and in Phase I clinical trials of heavily-pretreated patients with metastatic colorectal cancer. The conjugate, designed with a near-homogeneous drug substitution of 7?8 SN-38/MAb and with a linker that released 50% of the drug in ~ 20 h, showed significant antitumor effects compared to a non-targeted ADC in human tumor xenografts, which could be augmented in combination with bevacizumab. The advantage of fractionated dosing was demonstrated, with potential implications for the clinical dosing schedule. Biodistribution comparing IMMU-130 with labetuzumab showed that the conjugate cleared somewhat faster from the blood, but this did not affect tumor uptake and retention. The use of an ultra-stable linker in the conjugate design abrogated antitumor effects. A tolerability study in rabbits showed a high safety margin, with no-observed-adverse-effect level (NOAEL) corresponding to a cumulative human-equivalent protein dose of 40-60 mg/kg. The preclinical findings appear to be corroborated in two Phase I clinical trials, with high tolerability and evidence of antitumor activity, including objective responses. The impact of the ADC design on the utility of IMMU-130, tailored to a poorly-internalizing target, is discussed.