Ocean Biomedical (NASDAQ: OCEA) Celebrates Discovery of Bispecific Antibodies and Immune Checkpoint Inhibitors That Kill Glioblastoma Cells and Melanoma Cells, and Block the Metastasis of Malignant Melanoma Cells to the Lung by Over 90%
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 programed 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.
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 or 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.
“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.
“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
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The announced discoveries were based solely on laboratory and animal studies. Ocean Biomedical has not conducted any studies that show similar efficacy or safety in humans. There can be no assurances that this treatment will prove safe or effective in humans, and that any clinical benefits of this treatment is subject to clinical trials and ultimate approval of its use in patients by the FDA. Such approval, if granted, could be years away.
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