Abstract 523P
Background
The alpha fetoprotein (AFP) receptor is an oncofetal antigen and a novel target for cancer therapeutics, This receptor is highly expressed on the surface of common cancers including many breast, lung, colorectal, prostate, ovarian and hematological malignancies, but is not expressed on normal adult cells. By covalently conjugating a novel maytansine toxin to a recombinant human form of AFP we can selectively deliver the toxin payload to cancer cells while sparing normal cells. Since AFP is a human protein, there is reduced risk of any harmful immune reaction to AFP conjugates.
Methods
Four novel AFP-maytansine conjugates of differing drug-protein ratios were administered intravenously (IV) to mice bearing human colon carcinoma (COLO-205) xenografts, at doses previously determined to be safe. Seven days after implantation, mice with tumors greater than 150 mm3 were randomized to receive control (vehicle) or one of the 4 conjugates (10 animals/ group). Animals were treated daily for 2 weeks with 2 days of rest after 5 doses; tumor volume was assessed twice weekly for 60 days following implantation. In a separate study, the biodistribution (BD) of AFP-maytansine conjugate in the COLO-205 model was investigated after a single IV dose.
Results
All animals in the control group were dead by day 38 due to uncontrolled tumor growth. Statistically significant reduction in tumor volume was observed in all treatment groups compared to control beginning at Day 17 and lasting until all control animals were euthanized. In one of the conjugate groups, tumor reduction continued following treatment discontinuation with tumor volumes falling below the limit of detection in 9 of 10 animals. All 10 mice in this group survived through Day 60 with only minimal tumor growth during the last week of the study. In this group, tumor volume was statistically different from two other conjugates on Day 24 (p<0.0001) and from the third group on Day 35 (p=0.001). No signs of toxicity were observed in treated mice. The BD study showed maytansine and metabolite accumulation in the tumor, while bone marrow levels were below detection.
Conclusions
Results support the development of an AFP-maytansine drug conjugate as a highly effective, safe and targeted cancer therapy. Studies are underway to support a phase I clinical trial.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Southern Research Institute.
Funding
Alpha Cancer Technologies Inc.
Disclosure
I.A. Sherman: Financial Interests, Institutional, Stocks/Shares: Alpha Cancer Technologies Inc.. All other authors have declared no conflicts of interest.