Abstract
The properties of cell surface proteins targeted by antibody-drug conjugates (ADCs) have not been fully exploited; of particular importance are the rate of internalization and the route of intracellular trafficking. In this study, we compared the trafficking of HER2, which is the target of the clinically approved ADC ado-trastuzumab emtansine (T-DM1), with that of prolactin receptor (PRLR), another potential target in breast cancer. In contrast to HER2, we found that PRLR is rapidly and constitutively internalized, and traffics efficiently to lysosomes, where it is degraded. The PRLR cytoplasmic domain is necessary to promote rapid internalization and degradation, and when transferred to HER2, enhances HER2 degradation. In accordance with these findings, low levels of cell surface PRLR (∼30,000 surface receptors per cell) are sufficient to mediate effective killing by PRLR ADC, whereas cell killing by HER2 ADC requires higher levels of cell surface HER2 (∼106 surface receptors per cell). Noncovalently cross-linking HER2 to PRLR at the cell surface, using a bispecific antibody that binds to both receptors, dramatically enhances the degradation of HER2 as well as the cell killing activity of a noncompeting HER2 ADC. Furthermore, in breast cancer cells that coexpress HER2 and PRLR, a HER2xPRLR bispecific ADC kills more effectively than HER2 ADC. These results emphasize that intracellular trafficking of ADC targets is a key property for their activity and, further, that coupling an ADC target to a rapidly internalizing protein may be a useful approach to enhance internalization and cell killing activity of ADCs. Mol Cancer Ther; 16(4); 681-93. ©2017 AACR.
Highlights
Breast cancer remains a disease of high unmet medical need [1]
Internalization of prolactin receptor (PRLR) antibody was evident by the intracellular accumulation of primary antibodies, whereas HER2 antibody remained on the cell surface (Fig. 1A, top and bottom)
Monoclonal antibodies conjugated with tubulin polymerization inhibitors, ado-trastuzumab emtansine (T-DM1) and brentuximab vedotin, have been approved by the FDA, much remains to be learned about how to select the best targets for antibody–drug conjugates (ADCs) [2, 3, 42]
Summary
Breast cancer remains a disease of high unmet medical need [1]. Monoclonal antibodies have proven to be effective therapies for this disease, with two antibodies targeting HER2 (trastuzumab and pertuzumab) approved for treatment.Recently, antibody–drug conjugates (ADCs) were introduced into clinical practice with the goal of improving efficacy of antibody-based treatments [2, 3]. Breast cancer remains a disease of high unmet medical need [1]. Monoclonal antibodies have proven to be effective therapies for this disease, with two antibodies targeting HER2 (trastuzumab and pertuzumab) approved for treatment. Antibody–drug conjugates (ADCs) were introduced into clinical practice with the goal of improving efficacy of antibody-based treatments [2, 3]. ADCs are designed to selectively kill cancer cells by combining the specificity of a monoclonal antibody with the intracellular delivery of a highly potent cytotoxic agent that usually targets tubulin or DNA. ADC targets need to be selectively expressed on tumor cells versus vital normal cells and must be able to deliver sufficient amounts of ADC to the intended intracellular compartments to ensure efficient ADC processing and drug release [4].
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