Albumin-SN-38 Conjugate (AlbuCure) for Cancer Therapy
A novel protein-drug conjugate of human serum albumin chemically conjugated to SN-38, solubilizing the potent chemotherapeutic. This therapy has the potential to treat many tumors with poor prognosis, including pancreatic, lung, breast, colorectal, ovarian, sarcoma, head and neck cancer, urothelial malignancies, and others.
Many solid tumors have poor prognosis despite recent progress in molecularly targeted therapy and immunotherapy. Irinotecan/CPT-11, a chemotherapy on the WHO Essential Medicines List, is approved for use in colorectal cancer, lung cancer, pancreatic cancer, gastric cancer, malignant glioma, and sarcoma. However, only a small percentage of irinotecan is converted to its active metabolite SN-38 (3%), and the ability to achieve therapeutically effective plasma levels of SN-38 is further complicated by systemic circulation, liver uptake, and drug metabolism. SN-38 is 1,000 times more potent than irinotecan, yet cannot be delivered on its own due to poor solubility and high toxicity. Finding a more effective way to deliver this potent chemotherapeutic to the tumor microenvironment (TME) is urgently needed.
Dr. Terry Williams (oncologist, formerly of The Ohio State University and presently City of Hope) and Dr. Robert Lee (of The Ohio State University) have developed a novel albumin-SN-38 conjugate that significantly increases the solubility and availability of SN-38 (AlbuCure). In human pancreatic and lung cancer cell lines and mouse xenograft models, AlbuCure demonstrates high potency with relative safety, and also marked improvement over irinotecan. The researchers also identified caveolin-1 (Cav-1) as a potential predictive biomarker for treatment efficacy. Expression of Cav-1 (the principal structural component of caveolae) is upregulated in many tumor types and associated with poor prognosis. At the same time, caveolae-mediated endocytosis facilitates cellular uptake of albumin. Another albumin-based chemotherapy, nab-paclitaxel (Abraxane®), approved by the FDA to treat pancreatic, non-small cell lung, and breast cancers, has limited efficacy due to albumin and paclitaxel carried in the formulation falling apart easily. AlbuCure also represents a potential substantial improvement over this chemotherapy, by virtue of increased delivery of SN-38 to the TME, and may be particularly effective for tumors characterized by increased albumin uptake, including those with high Cav-1 expression or activated macropinocytosis (associated with KRAS mutations). The more stable protein-drug chemical conjugate by OSU researchers could potentially change the landscape of protein-drug conjugates in cancer therapy.
U.S. Application 63/223,797, filed 7/20/2022
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Robb R, Kuo J, Liu Y, Corrales-Guerrero S, Cuit T, Hegazi A, Nagy G, Lee RJ, Williams TM (2021). A Novel Protein-drug Conjugate, SSH20, Demonstrates Significant Efficacy in Caveolin-1 Expressing Tumors. Molecular Therapy Oncolytics, 22(24): 555-564. PMID: 34553040. PMCID: PMC8433067 https://doaj.org/article/6dbd85d6f99c4202b1a4bb0f11735547