Immunomedics (IMMU) Announces Positive Preclinical Data from IMMU-132 in SN-38-Resistant Cancer Cells
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Immunomedics, Inc. (Nasdaq: IMMU) announced that adding an inhibitor of ATP-binding cassette (ABC) transporters to sacituzumab govitecan, the Company’s lead antibody-drug conjugate (ADC) for solid cancer therapy, increased the median survival of mice bearing a SN-38-resistant human gastric cancer cell line. Results from this preclinical study were published in Molecular Cancer Therapeutics.1
Sacituzumab govitecan is a first-in-class ADC developed by the Company by conjugating the moderately-toxic drug, SN-38, site-specifically and at a high ratio of drug to hRS7, a humanized antibody that targets the Trop-2 receptor expressed by many solid cancers. This ADC has produced promising therapeutic results in some patients with metastatic solid cancers in an open-label, single arm Phase 2 study. Based on results from this mid-stage trial, the FDA has granted sacituzumab govitecan Breakthrough Therapy designation for the treatment of patients with triple-negative breast cancer who have failed prior therapies for metastatic disease, and the Company is working with the regulatory agency toward a potential accelerated approval in this disease setting.
A common cause of treatment failure in cancer therapy is multidrug resistance. In general, the occurrence of drug resistance in cancer cells can be intrinsic or acquired, with each type resulting from a variety of factors, such as decreased uptake of soluble drugs, activation of drug-detoxifying systems, modulation or mutation of drug targets, defective apoptosis pathways, and, above all, overexpression of the ABC transporters, which act by expelling drugs from the cell, thereby lowering the amount of drugs inside the cancer cells.
The objective of this preclinical study was to explore the use of known inhibitors of ABC transporters for improving the therapeutic efficacy of sacituzumab govitecan by overcoming SN-38-resistance. Human breast and gastric cancer cell lines were first made resistant to SN-38 by continuously exposing them to increased concentrations of SN-38 over a period of approximately 2 years. The two SN-38-resistant cell lines were shown to be 50-fold less responsive to SN-38 than their parental cells.
Treatment of both SN-38-resistant human cancer cell lines with known inhibitors of ABC transporters restored toxicity of SN-38. More importantly, when sacituzumab govitecan was combined with YHO-13351, an inhibitor of ABC transporter, in mice bearing SN-38-resistant human gastric cancer cell line, a statistically significant 64% improvement in median survival was achieved in comparison with untreated animals (P = 0.0278). Sacituzumab govitecan alone had a 29% improvement in median survival, while YHO-13351 showed no effect on its own. Although irinotecan plus YHO-13551 improved the survival of the mice, it did not reach significance (P = 0.0852).
Commenting on these preclinical results, Cynthia L. Sullivan, President and Chief Executive Officer stated, “These in vivo results suggest that suitable inhibitors that are tolerated well by the host animals can overcome ABC resistance and that the resistant tumor lines can become appreciably responsive to IMMU-132 and to a lesser extent to irinotecan.” Ms. Sullivan added, “We are pursuing further work to address the feasibility of preclinical testing for such drug resistance as a predictive bioassay to select patients who should receive ABC-blocking therapy with IMMU-132, in order to enhance the potency of IMMU-132 in cancer cells that are intrinsically or become resistant to SN-38.”
- Chang C-H, Wang Y, Zalath M, et al. Combining ABCG2 inhibitors with IMMU-132, an anti-Trop-2 antibody conjugate of SN-38, overcomes resistance to SN-38 in breast and gastric cancers. Molecular Cancer Therapeutics 15(8):1910–19, 2016.
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