The targeted delivery of drug by an antibody is an exciting approach in cancer treatment that has gained significant interest over the past few years. We believe our ADC programs differ from those of other companies, because we do not use supertoxic drugs, such as calicheamicin, for example. Instead, we specifically look for moderately-toxic drugs, such as SN-38 and doxorubicin. We believe the use of a less-toxic drug, conjugated to the appropriate tumor-targeting antibody, will permit greater delivery of the drug over repeated cycles of therapy, thereby improving the therapeutic index, or ratio of efficacy to toxicity, of the drug.
- S.V. Govindan and D.M. Goldenberg. Designing immunoconjugates for cancer therapy. Expert Opin Biol Ther. 2012 Jul;12(7):873-90. doi: 10.1517/14712598.2012.685153. Review. PMID: 22679911.
- Pretargeted immunoPET for imaging colorectal cancer in a mouse model. Proc. Soc. Nucl. Med. 56th Annual Meeting, R. Schoffelen, R. M. Sharkey, W. J. McBride, G. Franssen, A. Eek, P. Laverman, W. T. van der Graaf, W. J. Oyen, D. M. Goldenberg, O. C. Boerman. J. Nucl. Med. 50(Suppl 2): 100P (Abstr. #381), 2009.
Milatuzumab, our anti-CD74 antibody, conjugated with doxorubicin is the first ADC in our clinical pipeline. The scientific rationale for developing this agent is based on our understanding of the function and properties of CD74, which is expressed not only on many hematologic tumors, such as non-Hodgkin lymphoma, or NHL, and chronic lymphocytic leukemia, or CLL, but also on certain solid cancers. When milatuzumab binds to CD74, it internalizes rapidly, making it an ideal target for selectively delivering a high concentration of doxorubicin inside the cancer cells.
Another aspect that differentiates our ADC programs is the chemistry of our linker that attaches the drug to the antibody. The technology utilizes a pH-sensitive linker, which allows the rapid detachment of the drug once the ADC enters the acidic environment of the tumor cells. In the case of our milatuzumab-doxorubicin conjugate, the rapid internalization into target cells results in the catabolism of ~10 million molecules per cell per day, of the doxorubicin. Therefore, this ADC delivers a high concentration of the intact drug after intracellular release of the drug from the antibody.
Consequently, drugs delivered by milatuzumab do not have to be supertoxic, because the shuttle mechanism of CD74 loads the target cell with multiple copies of the drug. Furthermore, CD74 is involved in a cell-to-cell communication pathway that is critical for survival. When CD74 is blocked by milatuzumab, it can lead to cell death, or apoptosis. Thus, the therapeutic efficacy of milatuzumab-doxorubicin may be the combined cytotoxic effects of both the antibody and the drug.
Multiple Myeloma, NHL or CLL
Milatuzumab-doxorubicin is currently being evaluated in dose-escalation trials in patients with recurrent multiple myeloma and relapsed NHL or CLL.
- R. Stein, M.R. Smith, S. Chen, M. Zalath and D.M. Goldenberg. Combining milatuzumab with bortezomib, doxorubicin, or dexamethasone improves responses in multiple myeloma cell lines. Clin Cancer Res. 2009 Apr 15;15(8):2808-17. doi: 10.1158/1078-0432.CCR-08-1953. Epub 2009 Apr 7. PMID: 19351768.
Labetuzumab is our proprietary humanized antibody that targets the carcinoembryonic antigen, CEACAM5. This antigen is abundant at the site of virtually all cancers of the colon and rectum, and is associated with many other solid tumors, such as breast and lung cancers. We have conjugated labetuzumab with SN-38, the active metabolite of irinotecan (or CPT-111), the FDA-approved drug for metastatic colorectal cancer treatment. Although SN-38 is about 3 orders of magnitude more potent than irinotecan, it cannot be given directly to patients because of its toxicity and poor solubility. However, using the same linker technology as with milatuzumab-doxorubicin, we have produced antibody-SN-38 conjugates that are soluble in water with excellent yields, as well as preservation of antibody binding and drug activity. By linking SN-38 to labetuzumab, the drug can be delivered selectively to tumors, thereby increasing the amount reaching the tumors and minimizing damage to normal tissues and organs.
Labetuzumab-SN-38 is the second agent from our ADC program to enter clinical testing. The first human trial of this ADC is a dose-escalation study in heavily-pretreated patients with metastatic colorectal cancer . Since we did not observe any unexpected adverse events that would cause us to change our trial design, we have nevertheless opened a second study in the same disease setting using a different dosing frequency, in anticipation of achieving faster tumor responses from increased cumulative doses .
- N.H. Segal, J. Verghis, S. Govindan, P. Maliakal, R.M. Sharkey, W.A. Wegener, D.M. Goldenberg AND L.B. Saltz. A Phase I study of IMMU-130 (labetuzumab-SN38) anti-CEACAM5 antibody-drug conjugate (ADC) in patients with metastatic colorectal cancer (mCRC). Proc. Amer. Assoc. Cancer Res. 104th Annual Meeting, 54 (Suppl Late-Breaking): 54-55 (Abstr. #LB-159), 2013.
- S.J. Moon, F. Tat, A. Sheerin, M. Zalath, R. Arrojo, T.M. Cardillo, S.V. Govindan and D.M. Goldenberg. Cross-linker evaluation in the design of antibody-SN-38 conjugates for cancer therapy. Cancer Research: April 15, 2010; Volume 70, Issue 8, Supplement 1. Proc. Amer. Assoc. Cancer Res. 101st Annual Meeting, 51:591-592 (Abstr. #2349), 2010. doi: 10.1158/1538-7445.AM10-2439.
- S.V. Govindan, T.M. Cardillo, S.J. Moon, H.J. Hansen and D.M. Goldenberg. CEACAM5-targeted therapy of human colonic and pancreatic cancer xenografts with potent labetuzumab-SN-38 immunoconjugates. Clin Cancer Res. 2009 Oct 1;15(19):6052-61. doi: 10.1158/1078-0432.CCR-09-0586. Epub 2009 Sep 29. PMID: 19789330.
- S.J. Moon, S.V. Govindan, T.M. Cardillo, C.A. D’Souza, H.J. Hansen and D.M. Goldenberg. Antibody conjugates of 7-ethyl-10-hydroxycamptothecin (SN-38) for targeted cancer chemotherapy. J Med Chem. 2008 Nov 13;51(21):6916-26. doi: 10.1021/jm800719t. Epub 2008 Oct 22. PMID: 18939816.
Our third clinical program with an ADC is IMMU-132, involving hRS7, an internalizing humanized antibody that binds to the epithelial glycoprotein-1 antigen, or EGP-1, also known as human trophoblast cell-surface antigen, or TROP-2, again conjugated with SN-38. TROP-2 is a cell-surface receptor expressed by many human tumors, such as cancers of the breast, cervix, colon, rectum, liver, lung, pancreas, ovary, kidney, and prostate, but with only limited expression in normal human tissues.
hRS7-SN-38 is currently being evaluated in a multi-center dose-escalation trial in patients with bladder, breast, colorectal, esophageal, gastric, head and neck, hepatocellular, kidney, small-cell and non-small-cell lung, pancreatic, prostate or ovarian cancer.
- S.V. Govindan, T.M. Cardillo, F. Tat, R. Arrojo, R.M. Sharkey and D.M. Goldenberg. Optimal cleavable linker for antibody-SN-38 conjugates for cancer therapy: Impact of linker’s stability on efficacy. Cancer Research. April 15, 2012; Volume 72, Issue 8, Supplement 1. Proc. Amer. Assoc. Cancer Res. 103rd Annual Meeting, 53:611 (Abstr. #2526), 2012. doi: 10.1158/1538-7445.AM2012-2526.
- T.M. Cardillo, S.V. Govindan, R.M. Sharkey, P. Trisal and D.M. Goldenberg. Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res. 2011 May 15;17(10):3157-69. doi: 10.1158/1078-0432.CCR-10-2939. Epub 2011 Mar 3. PMID: 21372224.
- D.M. Goldenberg, R.M. Sharkey, H.W. Founds, P. Trisal, F. Tat, S.V. Govindan and T.M. Cardillo. Tolerability in mice, monkeys, and rabbits of new antibody (MAb)-drug (SN-38) immunoconjugates. Cancer Research: April 15, 2011; Volume 71, Issue 8, Supplement 1. Proc. Amer. Assoc. Cancer Res. 102nd Annual Meeting, 52:865 (Abstr. #3619), 2011. doi: 10.1158/1538-7445.AM2011-3619.
- S.V. Govindan, T.M. Cardillo, S-J Moon, F. Tat, A. Sheerin, M. Zalath, A. Nair, R.M. Sharkey, D.M. Goldenberg. Efficacious therapies of two human pancreatic cancer xenografts and an aggressive human lymphoma xenograft with redesigned antibody-SN-38 conjugates. Cancer Research: April 15, 2010; Volume 70, Issue 8, Supplement 1. Proc. Amer. Assoc. Cancer Res. 101st Annual Meeting, 51:591 (Abstr. #2348), 2010. doi: 10.1158/1538-7445.AM10-2438.