Anti-CLDN4/anti-CD137 bispecific antibody
Inventors
Tenda, Yoshiyuki • Yuri, Masatoshi • Yagi, Shigenori • Satake, Yoshiki • Hirayama, Kazunori • Shirai, Hiroki • Sasaki, Hiroki • CHIWAKI, Fumiko • Komatsu, Masayuki
Assignees
Astellas Pharma Inc • National Cancer Center Japan • National Cancer Center Korea
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Publication Number
US-12227586-B2
Publication Date
2025-02-18
Expiration Date
Abstract
An object of the present invention is to provide an anti-CLDN4/anti-CD137 bispecific antibody usable in treatment of cancer.An anti-CLDN4/anti-CD137 bispecific antibody produced using an anti-CLDN4 antibody binding to CLDN4 and an anti-CD137 antibody binding to CD137 had agonistic activity for CD137, promoted production of interferon γ by a T cell, and exhibited cytotoxic activity against a cancer cell expressing CLDN4 on a cell surface thereof. Besides, it was shown that the anti-CLDN4/anti-CD137 bispecific antibody can be safely administered to monkeys. Therefore, the anti-CLDN4/anti-CD137 bispecific antibody is usable in treatment of human cancer.
Core Innovation
The invention relates to an anti-CLDN4/anti-CD137 bispecific antibody comprising an anti-CLDN4 antibody heavy chain variable region and light chain variable region and an anti-CD137 antibody heavy chain variable region and light chain variable region. The anti-CLDN4 arm is provided as an IgG antibody comprising the anti-CLDN4 heavy chain variable region and the anti-CLDN4 light chain variable region, and the anti-CD137 arm is provided as an anti-CD137 single chain variable fragment (anti-CD137 scFv) containing the anti-CD137 heavy chain variable region and the anti-CD137 light chain variable region.
The anti-CLDN4 heavy chain variable region and light chain variable region are defined by specific CDR1, CDR2, and CDR3 amino acid sequences at defined amino acid positions of particular SEQ ID NOs, and the anti-CD137 heavy chain variable region and light chain variable region are likewise defined by specific CDR amino acid sequences at defined amino acid positions of particular SEQ ID NOs. The disclosure further characterizes additional bispecific antibody embodiments defined by specified anti-CLDN4/anti-CD137 polypeptide sequences.
The document further includes embodiments in which the anti-CD137 scFv is linked to an anti-CLDN4 IgG chain via an amino-terminal scFv connection to a heavy- or light-chain carboxy-terminus through a linker. It also includes polynucleotides encoding the specified anti-CLDN4 heavy-chain variable region and/or anti-CLDN4 light chain variable region and/or anti-CD137 components, for use with a host cell expressing an anti-CLDN4/anti-CD137 bispecific antibody.
Claims Coverage
The independent claims cover 2 main inventive antibody constructs for an anti-CLDN4/anti-CD137 bispecific antibody, including defined sequence and construct features.
Defined anti-CLDN4 and anti-CD137 variable-region CDR sequences in an IgG/scFv bispecific format
An anti-CLDN4/anti-CD137 bispecific antibody comprising an anti-CLDN4 antibody heavy chain variable region and light chain variable region, and an anti-CD137 antibody heavy chain variable region and light chain variable region, wherein the anti-CLDN4 heavy chain variable region and light chain variable region include defined CDR1/CDR2/CDR3 amino acid sequences at specified amino acid positions of particular SEQ ID NOs, the anti-CD137 heavy chain variable region and light chain variable region include defined CDR1/CDR2/CDR3 amino acid sequences at specified amino acid positions of particular SEQ ID NOs, and the bispecific antibody comprises an anti-CLDN4 IgG and an anti-CD137 single chain variable fragment (anti-CD137 scFv).
Specified-length anti-CLDN4 heavy-chain polypeptide including an anti-CD137 scFv and specified-length anti-CLDN4 light-chain polypeptide
An anti-CLDN4/anti-CD137 bispecific antibody comprising a polypeptide consisting of an amino acid sequence at amino acid positions 1-712 of SEQ ID NO: 38 containing a heavy chain of an anti-CLDN4 antibody and an anti-CD137 scFv, and a light chain of an anti-CLDN4 antibody consisting of an amino acid sequence at amino acid positions 1-215 of SEQ ID NO: 40.
Overall, the claim set covers anti-CLDN4/anti-CD137 bispecific antibodies defined by explicit CDR sequence and position constraints in an anti-CLDN4 IgG plus anti-CD137 scFv format, and an embodiment defined by specified full polypeptide spans for an anti-CLDN4 heavy-chain polypeptide containing an anti-CD137 scFv together with a specified anti-CLDN4 light-chain polypeptide.
Stated Advantages
CD137 signaling is activated only when co-engaged with CLDN4.
Induces T-cell interferon-gamma (IFN-gamma).
Results in cancer cell cytotoxicity.
Mitigates hepatotoxicity risk associated with anti-CD137 agonist antibodies such as urelumab.
Safety is reported after administration in cynomolgus monkeys.
Documented Applications
Anticancer agent activity against cancer involving CLDN4 on cancer cells and CD137 on immune cells, including T-cell IFN-gamma induction and cancer cytotoxicity.
Use in a mouse tumor model with reported tumor-volume reduction.
Administration in cynomolgus monkeys with reported safety.
Treatment method for cancer by administering the bispecific antibody to a subject where the cancer is a CLDN4-expressing cancer.
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