On September 6, 2022 Ocean Biomedical and Aesther Healthcare Acquisition Corp. ("Aesther") (NASDAQ: AEHA) reported the discovery of bispecific antibodies that target Chitinase 3-like-1 and immune checkpoint inhibitors, killing glioblastoma cells and melanoma cells, and blocking the metastasis of malignant melanoma cells to the lung by over 90% (Press release, Ocean Biomedical, SEP 6, 2022, View Source [SID1234619041]). Glioblastoma multiforme (GBM) is a deadly type of brain tumor and 5-year survival is just 8% for those aged 45-54. About 25% of GBM patients are not actively treated due to rapid disease progression. Malignant melanoma, the most serious skin cancer, can metastasize to other organs. Once it has spread to other organs it is difficult to treat. Metastatic melanoma (Stage IV) has 22.5% five year survival. Non-small cell lung cancer (NSCLC) is a major unmet medical need that accounts for 85% of pulmonary malignancies and effects approximately 450,000 individuals. In greater than 50% of affected patients the tumors are diagnosed at advanced stages with metastatic spread that precludes curative surgical resection.
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Background
Recent studies of NSCLC have highlighted genetic abnormalities that underlie these tumors. These genetic abnormalities generate abnormal proteins that have not been previously seen by the patient’s immune system which, in turn, activates antitumor immune responses that control tumor initiation and progression. Studies over recent years have demonstrated that tumor initiation and progression are often mediated by the ability of the tumors to produce immunosuppressive proteins and activate immunosuppressive pathways, called immune checkpoint inhibitors (ICPI), that allow tumor growth and progression by shutting off these critical anti-tumor immune responses. This includes the programmed death (PD) pathway including PD-1, PD ligand 1 (PD-L1) and PD-L2 and the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) pathway that includes CTLA4 and its binding partners B7.1/B7.2. Antibodies that target ICPI such as PD-1, PD-L1 and CTLA4 have been generated which have therapeutic efficacy in NSCLC and other tumors. Unfortunately, only a minority of patients respond to these therapies and the responses are often not durable.
Chitinase 3-like-1 (CHI3L1) is a member of the 18 glycosyl hydrolase gene family that is readily detected in the circulation of normal individuals and expressed at exaggerated levels in the circulation of individuals with diseases characterized by inflammation, tissue remodeling and or cancers.
Discoveries
Recent studies from our laboratory have demonstrated that CHI3L1 is a critical regulator of a number of key cancer-causing pathways. We have highlighted its ability to inhibit tumor cell death (apoptosis), its inhibition of the expression of the tumor suppressors P53 and PTEN and its stimulation of the B-RAF protooncogene. Most recently we have discovered that CHI3L1 is a "master regulator" of ICPI including key elements of the PD-1 and CTLA4 pathways. In accord with the importance of these pathways we have also generated antibodies: 1.) a monoclonal antibody against CHI3L1, and 2.) bispecific antibodies that simultaneously target CHI3L1 and PD-1 or CTLA4. The impressive ability of our bispecific antibodies to control primary and metastatic lung cancer in murine experimental modeling systems is discussed below.
We generated bispecific antibodies that simultaneously target CHI3L1 and PD-1 or CTLA4. We then compared their effects in experimental models in which T cells and tumor cells are cultured together (a co-culture system) and in a murine model of lung metastasis. In all cases we compared the effects of the bispecific antibody to control antibodies, and to individual monospecific antibodies against CHI3L1, PD-1 or CTLA4, alone or in combination and the results are shown in the figures below.
In the coculture system, critical immune regulating cells called T cells were placed in culture with cancer cells. The ability of the antibodies to induce T cell differentiation and kill (induce apoptosis) of the tumor cells were then evaluated. As can be seen in Figure 1 below, tumor cell death was not induced by isotype control antibodies, and modest degrees of tumor cell apoptosis were seen in cultures with monospecific antiCHI3L1, antiPD-1 or antiCTLA4 individually. Additive tumor cell death was seen when antiCHI3L1 was administered in combination with antiPD-1 and CTLA4 alone. Most importantly, highly impressive synergistic tumor cell death was seen when the cocultures were treated with the bispecific antibodies (FRGxCTLA4 or FRGxPD-1). In all cases the cell death that was induced was due to T cell differentiation into CD8+ cytotoxic T cells.
In the murine metastasis model we administered malignant melanoma cells into the murine circulation and evaluated their spread to the lungs and pleural surface by counting the number of black staining pleural metastasis. Tumor metastasis were readily appreciated in lungs from mice treated with isotype control antibodies, and modest decreases in metastasis were seen in lungs from mice treated with monospecific antiCHI3L1, antiPD-1 or antiCTLA4 individually. Additive inhibition of tumor spread was seen when antiCHI3L1 was administered in combination with antiPD-1 and CTLA4. Most importantly, highly impressive synergistic inhibition of tumor metastasis was seen in lungs from mice treated with the bispecific antibodies (FRGxCTLA4 or FRGxPD-1). Figure 2 below shows the results with the FRGxCTLA4 antibody.
Quoted
"Bispecific antibodies that simultaneously target CHI3L1 and ICPI like PD-1 and or CTLA4 have an impressive and synergic ability to induce tumor cell death and prevent tumor metastasis compared to individual antibody moieties," commented Dr. Jack A. Elias, Dean Emeritus of Medicine and Biological Sciences and Professor of Translational Science, Medicine and Molecular Microbiology and Immunology at the Warren Alpert Medical School Brown University; Scientific co-founder.
"Non-small cell lung cancer (NSCLC) is the leading cause of cancer death and second most diagnosed cancer in the US. Glioblastoma multiforme (GBM) is a lethal type of brain tumor that affects approximately 28,000 people in the U.S. The median survival time is about 15 months. With our discovery that CHI3L1 is a critical regulator of a number of key cancer-causing pathways by highlighting its ability to inhibit tumor cell death (apoptosis) this therapy has the potential to save thousand of lives of people effected from NSCLC and GBM," said Dr. Chirinjeev Kathuria, co-founder and Executive Chairman.
Suren Ajjarapu, Chairman and CEO of Aesther, commented, "Aesther is honored to be part of the exciting discovery announced by Ocean Biomedical today. We look forward to working with Ocean to bring these therapies to patients. This discovery and others will lead to long term shareholder value growth and appreciation."
About Aesther Healthcare Acquisition Corp.
Aesther is a special purpose acquisition company (SPAC) formed for the purpose of effecting a merger, capital stock exchange, asset acquisition, stock purchase, reorganization or similar business combination with one or more businesses. Its principals possess public and private market investing experience and operational knowledge to bring value added benefits to Ocean Biomedical. The Aesther team has substantial experience investing in and operating businesses in multiple sectors, as well as a significant long-term track record in creatively structuring transactions to unlock and maximize value.