KR-20260068125-A - ANTIBODIES BINDING AXL

Abstract

The present disclosure relates to an anti-AXL antibody, an immunoconjugate, a composition, and a method for treating cancer using such anti-AXL antibody, immunoconjugate, or composition.

Inventors

• 브레이, 에스더
• 사틴, 다비드
• 반 덴 브린크, 에드워드 노르베르트
• 베르질, 데니스
• 데 종, 로브 엔.
• 파렌, 파울
• 반 디크휘젠 라데르스마, 라임케

Assignees

• 젠맵 에이/에스

Dates

Publication Date

20260513

Application Date

20150710

Priority Date

20140711

Claims (1)

1. Human treatment methods.

Description

Antibodies binding to AXL The present invention relates to an antibody that binds to AXL, an immunoconjugate, a composition comprising said antibody or immunoconjugate, and the use of said antibody and immunoconjugate. The TAM subgroup of mammalian receptor tyrosine kinases (RTKs) consists of AXL, Tyro3, and Mer. AXL is a transmembrane protein of 104 to 140 kDa with the ability to convert [1]. AXL can be activated upon binding to its ligand, vitamin K-dependent growth arrest-specific factor 6 (Gas6). Binding of Gas6 to AXL results in AXL dimerization, autophosphorylation, and subsequent activation of intracellular signaling pathways, such as PI3K/AKT, mitogen-activated protein kinases (MAPK), STAT, and the NF-κB cascade [2]. In cancer cells, AXL enhances tumor cell motility, invasion, and migration, and is involved in epithelial-mesenchymal transition (EMT) [3]. Furthermore, AXL expression has been implicated in resistance to chemotherapy and targeted therapies, such as epidermal growth factor receptor (EGFR) targeted therapy (Wilson 2014, Brand 2013, Zhang 2012) or inhibitors of the B-raf (BRAF) pathway (Muller, 2014). The extracellular domain of the TAM receptor and its members consists of a combination of two N-terminal immunoglobulin (Ig)-like domains and two fibronectin type III (FNIII) repeats [1]. The ligand Gas6 binds to Ig-like domains I and II of AXL [14]. Upregulation of AXL has been reported in various cancers, including gastric cancer, prostate cancer, ovarian cancer, and lung cancer [1]. Furthermore, AXL is overexpressed in breast and pancreatic cancers and is significantly associated with a higher frequency of metastasis and poor overall survival [2]. Targeted inhibition of RTKs may be effective as an anti-tumor and/or metastasis therapy. Such targeted inhibition of AXL and/or its ligand Gas6 involves both small molecules and anti-AXL antibodies [3]. Anti-AXL antibodies have been described to attenuate non-small cell lung carcinoma xenograft growth in vivo by downregulating receptor expression, reducing tumor cell proliferation, and inducing apoptosis [4]. Furthermore, various monoclonal antibodies have been described to block the binding of the ligand Gas6 to AXL [2], [5], and [7]. Anti-AXL antibodies have been previously described [8] to [13]. However, there remains a need for anti-AXL antibodies with improved anti-tumor activity. Summary of the Invention The object of the present invention is to provide an anti-AXL antibody. Accordingly, in one aspect, the present invention relates to an antibody that binds to AXL that does not compete with the ligand Growth Arrest-Specific 6 (Gas6) for AXL binding. In another aspect, the present invention relates to a bispecific antibody comprising a first binding region of the antibody according to the present invention and a second binding region that binds to a target or epitope different from the first antigen-binding region. In another aspect, the present invention relates to an antibody or bispecific antibody according to the present invention, and an immunoconjugate comprising a therapeutic moiety, such as a cytotoxic agent, a chemotherapy drug, a cytokine, an immunosuppressant, an antibiotic, or a radioisotope. In another aspect, the present invention relates to a composition comprising an antibody, a bispecific antibody, or an immunoconjugate according to the present invention. In another aspect, the present invention relates to a pharmaceutical composition comprising an antibody, a bispecific antibody, or an immunoconjugate according to the present invention, and a pharmaceutically acceptable carrier. In another aspect, the present invention relates to a nucleic acid construct encoding an antibody according to the present invention. In another aspect, the present invention relates to an expression vector comprising one or more nucleic acid constructs according to the present invention. In another aspect, the present invention relates to a host cell comprising a vector according to the present invention. In another aspect, the present invention relates to a hybridoma that generates an antibody according to the present invention. In another aspect, the present invention relates to an antibody, a bispecific antibody, or an immunoconjugate according to the present invention for use as a medicine. In another aspect, the present invention relates to an antibody, a bispecific antibody, or an immunoconjugate according to the present invention for use in the treatment of cancer. In another aspect, the present invention relates to a method for treating cancer comprising administering an antibody, a bispecific antibody, an immunoconjugate, a composition, or a pharmaceutical composition according to the present invention to a subject in need thereof. In another aspect, the present invention relates to a method for diagnosing a disease characterized by the involvement or accumulation of AXL-expressing cells, comprising administering an antibody, a bispecific