Alpha Fetoprotein (AFP) is a Human Protein produced by the embryo during fetal development and serves two critical
- Normalizes Immune System responses so the mother’s immune system doesn’t attack the embryo. Symptoms of
autoimmune diseases: Inflammatory Bowel Disease (Crohn’s/Colitis), Myasthenia Gravis, MS, etc. go into remission
during pregnancy and this correlates very well with the rise and fall of AFP.
- Delivers nutrients from the maternal bloodstream to rapidly growing embryo. AFP binds these hydrophobic
nutrients and circulates with them until it finds AFP receptors which are present on all embryonic cells. It then
binds to the receptor and is transported into the cell where the payload is released. After birth, the production of
AFP stops, and the receptors disappear.
Alpha Cancer is targeting three key market opportunities with AFP:
- Immuno-Oncology | ACT-903 (AFP + Linker + Maytansine) – Targets on most solid and liquid tumors and myeloid-
derived suppressor cells (MDSCs)
- Radio Labelled Theranostics – 89Zr-ACT-101 (Diagnostic) and 177Lu-ACT-101 (Therapeutic)
- Immunomodulation | ACT-101 (AFP) – Polyindication Drug (Portfolio in a Product) – IBD (Crohn’s/Colitis), MG, Multiple
Sclerosis and 40+ other IgG-driven disease – (seeking to outlicense this platform).
Human alpha fetoprotein (AFP) is a very complex protein with 16 disulphide bridges required to make it functional. Many attempts to produce it in conventional bioreactors have failed. Our ACT- 101 is a non-glycosylated form of AFP currently produced by recombinant DNA technology in mammalian system. Work is ongoing on developing a microbial cell line capable of producing AFP in a conventional bioreactor system. ACT-101 differs from naturally occurring human AFP only in that it contains one amino acid substitution at amino acid 233 (glutamine for asparagine).
AFP has a complex tertiary structure with 16 disulphide bonds that holds it in a specific 3D configuration. Many papers report the significant difficulty in making AFP in cell-based systems. The yields were very poor, and the costs were prohibitive. ACT, working with a partner using AI has now developed a microbial cell system that can express recombinant form of AFP and can be made in conventional bioreactors. This cell system is covered by brand new patents.
- Cancer can be viewed as a reversal to an embryonic state.
- AFP receptors are re-expressed on cancer cells as well as on Myeloid Derived Suppressor cells (MDSCs).
- AFP receptors are uniquely present on over 80% of cancers (including colorectal, ovarian, breast, prostate, lung, lymphoma, melanoma among many others).
- AFP receptors are also present on myeloid derived suppressor cells (MDSCs) that are recruited by solid tumors to shield them from recognition and attack by the immune system.
- AFP receptors are NOT present on normal healthy cells – therefore by attaching a payload to ACT-101, we can selectively destroy cancer cells and MDSCs while sparing normal cells.
- By attaching a chemotherapy payload to AFP we can selectively deliver chemotherapy to cancer cells and MDSCs while bypassing normal cells.
- This results in direct targeting and killing of cancer cells as well as activation of the immune system as a result of killing MDSCs, delivering a one-two punch to cancer cells with minimal or no toxicity.
A biotechnology company developed an AFP receptor assay which they hoped they could use as a diagnostic test for cancer patients. They had a collaboration with Abbott Laboratories who sent them hundreds of blinded samples of benign tumor tissue, cancer tissue and healthy tissue. Their test had a 93% sensitivity and specificity for cancer with no false positives. These findings have also been supported by significant literature and in our own in-vitro and in-vivo studies. After screening dozens of cancer cell lines, we found only one – a Molt-4 leukemic cell line that does not express the AFP receptor. We now use this cell line as a negative control.
Maytansine was selected because it is 1000-fold more potent than first generation toxins such as doxorubicin and has been clinically validated including the leading approved antibody drug conjugate Kadcyla®.
Depending on the selected first indication to be pursued and the results of the clinical trials throughout the development of ACT-903, ACT plans to apply for all relevant FDA designations and programs. These potential programs include Orphan Drug Designation (ODD), Fast Track
Designation (FTD), Breakthrough Therapy Designation (BTD) Accelerated Approval (AP) and/or Priority BLA Review (PR).
The rationale for use of rhAFP as a targeting agent for delivery of highly potent payloads such as maytansines to tumors is based on the high expression of the receptor for AFP on tumors and low or absent expression on healthy tissue. The receptor is also expressed on myeloid-derived suppressor cells, so by killing them the immune system can be unleashed to target the cancer as well. The result is a dual-pronged therapy with targeted lethality.
Clinical studies in over 300 patients demonstrated excellent safety without any serious adverse events at doses up to 100mg/week over months. No neutralizing antibodies were found in any of the patients. In previous toxicology studies of ACT-101 in rodents, neutralizing antibodies to AFP were detected. Toxicology studies were conducted in marmosets and showed low titers of neutralizing antibodies in about 50% of animals to recombinant human AFP following dosing once every 72 hours for 26 weeks (approximately 60 total doses).
AFP stabilizes beta-2 microglobulin (B2M) causing its expression to rise Increase in B2M expression impacts a series of HLA complexes through the MHC class 1 molecules. Prof. Blumberg, at Harvard University, discovered that AFP has potential to interfere with the IgG binding site – made famous by Immunovant, Argenx or Alexion – but goes on to say this is not the major effect.
Pre-clinical and clinical data support a number of indications. They include Myasthenia Gravis, Hashimoto Disease, IBD (Crohn’s/Colitis), Multiple Sclerosis with further expansion to over 100 ultra-rare, rare and orphan diseases. Where IVIG is used we believe that ACT-101 will be effective.