Immunomedics, Inc. (Nasdaq:IMMU), a biopharmaceutical company focused on developing monoclonal antibodies to treat cancer and other serious diseases, today reported results from two studies on the development of ribonuclease-based immunotoxins at the American Association for Cancer Research conference.
Ribonucleases (RNases) are naturally-occurring enzymes that break down ribonucleic acids. When used as potential anti-tumor agents, RNase causes cell death by inhibiting protein synthesis within living cells. The potency of RNase can be enhanced by linking it to tumor-targeting antibodies, as has been demonstrated by the Company for ranpirnase (Rap), an amphibian RNase, fused to milatuzumab, a humanized anti-CD74 antibody. (Please refer to the Company's press release at www.immunomedics.com/news_pdf/2005_PDF/PR12152005.pdf for more information).
New classes of antibody-Rap conjugates were generated in the current studies using the Company's patented Dock-and-Lock (DNL) technology, with each conjugate containing 4 copies of Rap linked to a specific site on an antibody. The first study reported at the conference focused on the Company's three proprietary humanized antibodies that target antigens on B-cell lymphomas and leukemias: epratuzumab (anti-CD22), veltuzumab (anti-CD20) and IMMU-114 (anti-HLA-DR). Labetuzumab (anti-CEACAM5), which does not target B-cells, was used as a control.
The ability to cause cell death was evaluated in three non-Hodgkin's lymphoma (NHL) and three acute lymphoblastic leukemia (ALL) cell lines. CD20 is expressed at a considerably higher surface density than CD22 in each of the NHL cell lines. However, the internalization rate for epratuzumab is much faster than veltuzumab. Among the three ALL cell lines used in this study, the relative antigen density is similar, with HLA-DR much higher than CD22, which is greater than CD20.
None of the parental antibodies, either alone or in combination with Rap, were cytotoxic in these assays. For each ALL cell line used, IMMU-114-Rap, which targets the most abundant antigen (HLA-DR), gave the most potent response, and was about 50-fold more active than the epratuzumab conjugate. ALL cell lines have very low CD20 antigen density. As a result, veltuzumab-Rap showed only modest cytotoxicity, similar to that of the non-targeting labetuzumab-Rap. These results suggest that the abundance of targeted antigen on cell surface is a critical factor for the potency of the antibody-Rap conjugates. Additionally, in all three NHL cell lines studied, veltuzumab-Rap was more potent than epratuzumab-Rap, which not only corroborated that antigen density is important but also indicated that it is more critical than internalization rate. Noteworthy, the veltuzumab conjugate exhibited very potent activity against a rituximab-resistant mantle cell lymphoma cell line.
The second study presented at this AACR meeting was on the development and characterization of a Rap conjugate of hRS7, an internalizing, humanized, anti-TROP-2 antibody owned by the Company. The growth inhibitory properties of hRS7-Rap were evaluated against breast, cervical, colorectal, lung, pancreatic, and prostate tumor cells, all of which express TROP-2.
hRS7-Rap was found to be very potent, showing activity in the sub-nanomolar range, which was 1,000- to 10,000-fold lower than Rap when used alone or in combination with hRS7. No toxicity, however, was observed for the immunotoxin in a prostate cancer line that fails to bind hRS7. Thus, the cell binding data suggest that the sensitivity of a cell line to the Rap conjugate of hRS7 appears to correlate with its TROP-2 expression on the cell surface. Based on these results, further in vivo studies are in progress to better determine the efficacy of hRS7-Rap for future development as a new therapeutic candidate for TROP-2-positive solid cancers.
"Once again, we have successfully applied DNL to generate a new class of agents for targeted cancer therapy," remarked Cynthia L. Sullivan, President and CEO. "We believe these initial results suggest that our novel immunotoxins have the potential to become therapeutic agents for a wide variety of human cancers."
CONTACT: Immunomedics, Inc.