Abstract PO077: BT7480, a novel fully synthetic tumor-targeted immune cell agonist (TICA™) induces tumor localized 4-1BB agonism
| العنوان: | Abstract PO077: BT7480, a novel fully synthetic tumor-targeted immune cell agonist (TICA™) induces tumor localized 4-1BB agonism |
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| المؤلفون: | Marianna Kleyman, Jun Ma, Kevin Mcdonnell, Philip Brandish, Sailaja Battula, Johanna Lahdenranta, Punit Upadhyaya, Elizabeth Repash, Eric Haines, Nicholas Keen, Kristen Hurov, Liuhong Chen, Jessica Kublin |
| المصدر: | Cancer Immunology Research. 9:PO077-PO077 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, biology, Chemistry, medicine.medical_treatment, Immunology, CD137, Immunotherapy, Tumor antigen, Immune system, Cancer immunotherapy, medicine, biology.protein, Cancer research, Interferon gamma, Cytokine secretion, Antibody, medicine.drug |
| الوصف: | Harnessing costimulatory molecules expressed on T and NK cells namely 4-1BB (CD137/TNFRSF9) is ideal for cancer immunotherapy. Despite promise preclinically, 4-1BB agonistic antibodies, were unable to demarcate hepatoxicity from efficacy in the clinic. Bispecific approaches promote target-mediated clustering of 4-1BB while limiting systemic and liver toxicity. Bicycles® are novel, fully synthetic, constrained bicyclic peptides with high affinity and selectivity to their targets. Their small size (~2kDa) and tunable pharmacokinetic parameters allow Bicycles to have superior tumor penetration and de-risk hepatoxicity concerns due to a renal clearance mechanism. We hypothesized that clustering and activation of 4-1BB could be attained by conjugating a 4-1BB binding Bicycle to a tumor antigen targeting Bicycle promoting a potent tumor-localized immune response. BT7480 is a tumor-targeted immune cell agonist (TICA™) targeting Nectin-4 and agonizing 4-1BB. Nectin-4 (PVRL4) is highly expressed in numerous tumor indications with unmet clinical needs. In an engineered 4-1BB reporter system, we found BT7480 induced potent 4-1BB agonism correlating to target antigen surface expression on the co-cultured tumor cells. Moreover, BT7480 induces cytokine secretion, including interleukin-2 and interferon gamma, in immune cell co-culture in the presence of tumor antigen. This activity is strictly dependent on Nectin-4 expression on tumor cells and the ability of the TICA to bind to both Nectin-4 and 4-1BB. In a MC38 (Nectin-4-expressing) syngeneic mouse model, intermittent dosing of BT7480 led to robust anti-tumor efficacy (22 out of 24 complete responders (CRs)). Importantly, a memory response was established in CR mice as resistance to a re-challenge with MC38 tumors was observed. Additionally, BT7480 led to increased intratumoral T cell infiltration without elevation of liver enzymes in a CT26 (Nectin-4-expressing) syngeneic mouse model. In non-human primates (NHPs), BT7480 exhibits dose linear exposure and is well tolerated up to 10mpk. BT7480 represents a new generation of chemically synthetic tumor antigen targeted 4-1BB agonists with potent efficacy and a favorable safety profile. Citation Format: Elizabeth M. Repash, Punit Upadhyaya, Johanna Lahdenranta, Jessica Kublin, Jun Ma, Marianna Kleyman, Liuhong Chen, Eric Haines, Sailaja Battula, Kevin McDonnell, Kristen Hurov, Philip Brandish, Nicholas Keen. BT7480, a novel fully synthetic tumor-targeted immune cell agonist (TICA™) induces tumor localized 4-1BB agonism [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO077. |
| تدمد: | 2326-6074 2326-6066 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::5b84741692db9ff257ff84f0606f14f6 https://doi.org/10.1158/2326-6074.tumimm20-po077 |
| رقم الأكسشن: | edsair.doi...........5b84741692db9ff257ff84f0606f14f6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23266074 23266066 |
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