Isolated antigen-binding protein and application thereof

Inventors

Zhang, Xin • Xu, Ting • Ma, Hui • YUAN, Yangyang • NING, Shanshan • FU, Shilong • PAN, Xiaolong • ZHOU, Liyao • Zhao, Meng • SHI, Erxia

Abstract

An isolated antigen-binding protein, having one or more of the following properties: 1) capable of binding to human and monkey-derived GITR proteins at a KD value of 7×10−12 or below, wherein the KD value is measured by BLI method; 2) capable of stimulating immune cell proliferation; 3) capable of stimulating immune cells to secrete IFN-γ, wherein the secretion is measured in T cell viability assay; 4) capable of inhibiting tumor growth and/or tumor cell proliferation; 5) capable of activating GITR signaling pathway; 6) capable of inhibiting the binding of GITR to GITRL.

Core Innovation

The invention relates to an isolated antigen-binding protein for binding to human and monkey-derived GITR proteins with a KD value of 7×10^-12 M or below, wherein the KD value is measured by Bio-Layer Interferometry (BLI). The isolated antigen-binding protein is also capable of stimulating immune cell proliferation and stimulating immune cells to secrete IFN-γ, and it activates the GITR signaling pathway.

The invention further relates to an isolated antigen-binding protein capable of inhibiting tumor growth and/or tumor cell proliferation and inhibiting the binding of GITR to GITRL. The antigen-binding protein includes VH comprising HCDR3 as set forth in SEQ ID NO: 4, HCDR1 as set forth in SEQ ID NO: 2, and HCDR2 as set forth in SEQ ID NO: 3, and VL comprising LCDR1 as set forth in SEQ ID NO: 10, LCDR2 as set forth in SEQ ID NO: 11, and LCDR3 as set forth in SEQ ID NO: 12.

The invention encompasses embodiments in which the VH and VL sequence architecture is defined by the specified CDR assignments, and additional framework-region requirements and constant-region origin are provided. Exemplary embodiments include humanized antibody formats derived from a parent murine-derived antibody (3E2), with binding affinity and functional readouts measured by BLI, NFκB signaling, T-cell proliferation, and IFN-γ increases.

Claims Coverage

The independent claim covers isolated antigen-binding proteins defined by direct binding to human and monkey-derived GITR at a specified BLI KD threshold, together with functional immune modulation and tumor effects. The coverage is anchored by eight inventive features, plus strict VH and VL CDR sequence assignments via SEQ ID NOs.

Overall, the claim coverage is focused on isolated antigen-binding proteins that bind human and monkey-derived GITR with a BLI KD of 7×10^-12 M or below and that functionally modulate immunity and tumor growth through stimulation of immune proliferation and IFN-γ secretion, activation of GITR signaling, inhibition of tumor growth/cell proliferation, and inhibition of GITR–GITRL binding. The proteins are further defined by specific VH and VL CDR sequence assignments set forth by SEQ ID NOs.

Stated Advantages

Documented Applications