On December 6, 2022 INmune Bio, Inc. (NASDAQ: INMB) (the "Company"), a clinical-stage immunology company focused on developing treatments that harness the patient’s innate immune system to fight disease, reported it has been invited to present data on the combination of INB03 and trastuzumab-deruxtecan (TDxd) for treatment of HER2 positive breast cancer (Press release, INmune Bio, DEC 7, 2022, View Source [SID1234624896]). The data suggests INB03, a dominant-negative TNF inhibitor that selectively sequesters soluble TNF (sTNF), may provide a novel mechanism for reversing resistance to HER2 targeted immunotherapy, and through this mechanism, may further enhance efficacy and reduce toxicity associated with TDxd treatment in some patients. TDxd is a trastuzumab-based antibody drug conjugate used to treat certain patients with HER2 breast cancer.

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Mucin 4 (MUC4), an easily measured glycoprotein on the cell surface of some HER2 positive breast cancer, is a biomarker of resistance to immunotherapy, including trastuzumab, and is also a biomarker of poor survival in women with HER2+ breast cancer. Expression of MUC4 is believed to be driven by soluble TNF produced by breast cancer cells. MUC4 is at the root of therapy resistance as it causes steric hinderance and prevents binding of trastuzumab to HER2 receptors and further promotes an immunosuppressive tumor microenvironment (TME). Dr. Schillaci has previously shown that INB03 downregulates MUC4 and reverses resistance to trastuzumab in MUC4 expressing HER2+ breast cancers. Prior to this data, it was not known if MUC4 expression by HER2 positive breast cancer has an impact on response to TDxd.

Using the well-established nude mouse model of HER2 resistance in mice with MUC4 expressing HER2+ breast cancer, JIMT-1 tumors exhibit decreased growth when treated with TDxd. The combination of TDxd with INB03 improved anti-tumor immunology of the TME with fewer myeloid derived suppressor cells (MDSC) and more antitumor tumor macrophages, which further decreased tumor growth compared to TDxd alone. Importantly, the addition of INB03 did not increase the toxicity of TDxd in these animals.

"Our data in a trastuzumab multi-resistant model of HER2 positive breast cancer shows that the resistance mechanisms observed with trastuzumab immunotherapy persist with trastuzumab-deruxtecan treatment," said Dr. Roxana Schillaci of Instituto de Biología y Medicina Experimental in Buenos Aires. "However, neutralizing soluble TNF with INB03 overcomes these resistance mechanisms and may promote an improved response to TDxd in women with trastuzumab-resistant disease, and may further provide opportunity for treatment with other types of immunotherapy."

% tumor growth inhibition of JIMT-1 tumor by volume No TDxd TDxd 1.25mg TDxd 2.5mg TDxd 5.0mg
no INB03 0 % 37 % 61 % 81 %
plus INB03 0 % 73 % 81 % 98 %
Increased antitumor effect with combination therapy NA 97 % 33 % 21 %

Poster ID: P1-11-12
Poster Title: Soluble TNFα blockade enhances trastuzumab deruxtecan antitumor effect in HER2-positive breast cancer
Date: Tuesday December 6, 2022
Time: 5:00 PM – 6:15 PM

"Trastuzumab-deruxtecan has revolutionized the treatment of women with HER2+ breast cancer, but 50% of women who receive the therapy for metastatic disease progress after two years," said RJ Tesi, MD, CEO of INmune Bio. "MUC4 expression is an easily determined biomarker that predicts resistance to trastuzumab based immunotherapy. Adding INB03 reverses the resistance mechanisms and may improve response to therapy, opening the door to treatment with other immunotherapies and may offer an opportunity to decrease toxicity of those immunotherapies in these patients," concluded Dr. Schillaci.

About INB03

INB03 is a Dominant Negative Tumor Necrosis Factor (DN-TNF) inhibitor that neutralizes soluble TNF (sTNF) without affecting trans membrane TNF (tmTNF) or TNF receptors. Compared to currently available non-selective TNF inhibitors, INB03 preserves the immune response to cancer by decreasing immunosuppressive cells in the TME including TAM and MDSC while promoting recruitment of anti-tumor immune cells including cytolytic CD8+ lymphocytes, NK cells and anti-tumor macrophages. INB03 has completed an open label dose-escalation Phase I trial in patients with advanced cancer. In that trial, INB03 was found to be safe and well tolerated – no dose limiting toxicity was found. INB03 decreased blood biomarkers of inflammation in patients with advanced cancer. INmune is seeking non-dilutive funding and/or a partnership to fund a Phase II trial that uses INB03 as part of combination therapy.