High anti-tumor activity of a novel alpha-fetoprotein-maytansinoid conjugate targeting alpha-fetoprotein receptors in colorectal cancer xenograft model

Abstract

The alpha-fetoprotein receptor (AFPR) is a novel target for cancer therapeutics. It is expressed on most cancers and myeloid derived suppressor cells (MDSCs) but generally absent on normal tissues. Studies were performed to investigate the use of recombinant human AFP (ACT-101) conjugated with maytansinoid toxins for targeted toxin delivery to cancer. Four structurally different ACT-101-maytansinoid conjugates containing cleavable glutathione sensitive linkers were initially investigated in a mouse xenograft model of colorectal cancer. Reduction in tumor volume was seen for all four conjugates compared to control (p < 0.05). The anti-tumor effects of the conjugate selected for further development (ACT-903) persisted after treatment discontinuation, with tumors becoming undetectable in 9 of 10 mice, and all 10 mice surviving through Day 60 with no obvious signs of toxicity. A follow-up study performed in the same model compared the effects of single intravenous doses of ACT-903 (10–50 mg/kg) to that of control groups receiving vehicle or ACT-101. A significant reduction of tumor burden compared to control was achieved in the 40 and 50 mg/kg dose groups. Survival was significantly prolonged in these 2 groups (40 mg/kg (p < 0.0001); 50 mg/kg (p = 0.0037). Free maytansine blood levels at 4 h were 0.008% of the dose, indicating stability of the conjugate in circulation as was expected based on in vitro plasma stability studies. No obvious signs of toxicity were seen in any of the treated groups. Observed efficacy and excellent tolerability of ACT-903 in these xenograft models support advancing the development of ACT-903 toward clinical use.

Alpha-Fetoprotein: A Revolutionary Anti-Cancer Drug

“…The conjugate is stable in circulation with no signs of toxicity. 41 Observed efficacy and excellent tolerability of ACT-903 in the ovarian xenograft models, consistent with prior research using colorectal xenograft models, support advancing its development toward clinical use. The NCr-nu/nu mice have no adaptive immune system.…”

“…40 Recombinant AFP (ACT-101, Alpha Cancer Technologies Inc.) injections did not accelerate tumor growth in immune-compromised animals, but they slightly reduced survival compared to control. 41 Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. 42 The 5-year HCC-specific survival of patients not receiving surgery was 14.7% for AFP-negative patients versus 6.1% for AFP-positive patients.…”

Structural characteristics of alpha-fetoprotein, including N-glycosylation, metal ion and fatty acid binding sites

“…ACT-903, an anti-tumor drug developed by Alpha Cancer Technologies Inc., is a conjugate of AFP and maytansine. It has been demonstrated to effectively improve the survival of xenograft mice without obvious signs of toxicity 54 . Although there have been numerous studies on the combination of AFP and drugs for tumor treatment, the binding mechanism and mode of action of AFP with drugs have scarcely been addressed.…”

The role of alpha-fetoprotein in the tumor microenvironment of hepatocellular carcinoma

“…Besides, recombinant AFP fragment derived from AFP domain-3 was found to suppress tumor cell growth. Various anticancer drugs exhibited therapeutic prospects when combined with AFP or AFP fragments, such as carminomycin, doxorubicin, paclitaxel, sorafenib, and maytansinoid (98)(99)(100)(101)(102)(103). Moreover, AFP can activate downstream signaling pathways, such as PI3K/Akt in tumor cells, promoting proliferation, survival, and migration (22,104).…”