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• W4308394503 abstract "<h3>Background</h3> 4-1BB is an immune costimulatory receptor. Anti-4-1BB agonistic monoclonal antibodies have high potential of therapeutic efficacy in cancers. However, 4-1BB agonistic antibody urelumab shows dose-limiting hepatotoxicity in clinical trials. B7-H4 is a member of the B7 superfamily. It shows limited expression in most normal tissues but high expression on the surface of tumor cells in breast, ovarian, and endometrial cancers. B7-H4 also inhibits the proliferation and activation of T cells. Blockade of B7-H4 demonstrates some efficacy in mouse models. To overcome the hepatotoxicity of systemically active 4-1BB agonist and to improve the anti-tumor activity of B7-H4 antagonist, HBM7008, a B7-H4x4-1BB bispecific antibody specifically activated in tumor microenvironment, has been developed. <h3>Methods</h3> B7-H4 expression of multiple tumor tissues was evaluated by immunohistochemistry staining. Anti-B7-H4 fully human IgG antibodies and anti-4-1BB fully human heavy chain only antibodies (HCAb) were generated from H2L2 and HCAb Harbour Mice®, respectively. HBM7008 was developed from Harbour BioMed HCAb based bispecific immune cell engager (HBICE®) platform. It is composed of anti-B7-H4 IgG1 monoclonal antibody and anti-4-1BB HCAb variable domain fused at the C-terminus of heavy chain constant region with LALA (L234A and L235A) mutations. Its proposed mechanism of action and nonclinical pharmacology were characterized by a series of <i>in vitro</i> and <i>in vivo</i> assays. <h3>Results</h3> B7-H4 showed high prevalence of expression on breast, ovarian, cervical, endometrial cancers, and squamous non-small-cell lung carcinoma. HBM7008 can bind to B7-H4 and 4-1BB simultaneously. HBM7008 robustly induced T cell activation <i>in vitro</i> in a B7-H4-dependent manner with activity comparable to that of urelumab. HBM7008 demonstrated potent antitumor activity with complete response and resistance to tumor rechallenge in a mouse model. It also increased proliferation of tumor infiltrating lymphocyte (TIL) cytotoxic CD8+ T and effector memory CD8+ T cells. HBM7008 is a first-in-class bispecific T cell engager targeting both B7-H4 and 4-1BB and enhances T cell function by dual mechanisms: (1) blockade of the B7-H4 mediated T cell inhibition and (2) activation of 4-1BB+ T cells only in a B7-H4 cross-linking dependent manner. In a good laboratory practice-compliant non-human primate 4-week repeat dose toxicity study, HBM7008 was well tolerated up to 100 mg/kg with no discernable drug-related toxicity. <h3>Conclusions</h3> HBM7008 demonstrated comparable biological activity to urelumab and improved safety profile characterized by <i>in vitro</i> functional assays, <i>in vivo</i> antitumor efficacy model, and TIL analysis. These preclinical data support the clinical investigation of HBM7008 for the treatment of cancers. <h3>Ethics Approval</h3> The cancer tissue microarray was purchased from Fanpu Biotech, Inc. The company ensured ethical approval from the patients, and patient consent for publication. The anti-tumor efficacy and pharmacodynamics studies in mice were approved by the internal ethics board of the respective contract research organization (CRO). The good laboratory practice-compliant toxicity studies in non-human primate were approved by Ethics Board of an appropriate contract research organizations (CROs)." @default.
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• W4308394503 date "2022-11-01" @default.
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• W4308394503 title "1057 HBM7008, a first-in-class bispecific antibody targeting both B7-H4 and 4–1BB, exhibits robust anti-tumor immunity and low toxicity through B7-H4-directed 4–1BB activation" @default.
• W4308394503 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1057" @default.
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