Anti-TSPAN8/anti-CD3 bispecific antibody and anti-TSPAN8 antibody
Inventors
Tenda, Yoshiyuki • Yuri, Masatoshi • Yamajuku, Daisuke • Tsutsumi, Takeshi • KUSUZAKI, Yuko • Sasaki, Hiroki • CHIWAKI, Fumiko • Komatsu, Masayuki
Assignees
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Publication Number
US-12304951-B2
Publication Date
2025-05-20
Expiration Date
Abstract
An objective of the present invention is to provide an anti-TSPAN8/anti-CD3 bispecific antibody and an anti-TSPAN8 antibody usable in treatment or prevention in human. A human monoclonal antibody producing mouse was immunized with a peritoneal disseminated cancer cell isolated from a patient, to obtain an antibody 16B11 and an antibody 16B12 that selectively bind to a peritoneal disseminated cancer cell. These antibodies were anti-TSPAN8 antibodies that bind to the region from amino acid positions 126 to 155 of TSPAN8 and exhibited strong binding activity to TSPAN8 expressed in the peritoneal disseminated cancer cell. Further, an anti-TSPAN8(16B11)-anti-CD3 bispecific antibody produced based on the sequence of 16B11 exhibited a cytotoxic activity against the TSPAN8-expressing cancer cell in vitro, exerted an anti-tumor action on TSPAN8-expressing cancer cell-bearing mice in vivo, and extended the lifetime of peritoneal dissemination model mice.
Core Innovation
The disclosed anti-TSPAN8 antibodies or antigen-binding fragments are defined by specific heavy chain variable region CDRs and light chain variable region CDRs, with CDR1, CDR2, and CDR3 provided as amino acid sequences within defined amino acid position ranges of given SEQ ID NOs. Two alternative sets of CDR/SEQ ID combinations are described, each comprising a heavy chain variable region with a CDR1, CDR2, and CDR3 defined by amino acid position ranges, and a light chain variable region with a CDR1, CDR2, and CDR3 defined by amino acid position ranges.
The disclosure further recites anti-TSPAN8 antibodies or antigen-binding fragments having specific post-translational modifications on the heavy chain variable region, including pyroglutamylation at the VH N-terminus and/or lysine deletion at the VH C-terminus. In addition to the antibody itself, the disclosure includes anti-TSPAN8 fusion proteins, antibody complexes or ADCs, and cells expressing anti-TSPAN8 on their surface, including CAR-T-like surface expression configurations using an anti-TSPAN8 targeting component.
The disclosure also describes immune targeting configurations using T/NK-cell surface antibodies, notably anti-CD3, where antibody forms and components are combined with anti-TSPAN8 targeting. Pharmaceutical composition and cancer treatment uses are described in connection with administering anti-TSPAN8 antibodies or antigen-binding fragments, including formats such as antibody complexes or ADCs and radioisotope-labeled antibody formats.
Claims Coverage
The provided claim set primarily covers anti-TSPAN8 antibody or antigen-binding fragments defined by specified heavy and light chain CDR segments from particular SEQ ID NOs, and corresponding polynucleotides encoding the defined heavy- and light-chain variable regions, with additional dependent coverage for pharmaceutical composition elements, post-translational modifications on the antibody heavy chain variable region, and implementation by expression vectors, transformed host cells, and culturing to produce the antibody or antigen-binding fragment.
Cdr-defined anti-TSPAN8 antibody or antigen-binding fragment
An anti-TSPAN8 antibody or an antigen-binding fragment comprising a heavy chain variable region with CDR1, CDR2, and CDR3 amino-acid sequences defined by amino acid position ranges within SEQ ID NOs 4 or 10, and a light chain variable region with CDR1, CDR2, and CDR3 amino-acid sequences defined by amino acid position ranges within SEQ ID NOs 8 or 12.
Polynucleotide encoding anti-TSPAN8 variable regions
A polynucleotide encoding an anti-TSPAN8 antibody heavy chain variable region consisting of an amino acid sequence from amino acid positions 1 to 121 of SEQ ID NOs 4 or 10 and/or a polynucleotide encoding an anti-TSPAN8 antibody light chain variable region consisting of an amino acid sequence from amino acid positions 1 to 107 of SEQ ID NOs 8 or 12.
The provided claim set primarily covers anti-TSPAN8 antibody or antigen-binding fragments defined by specified heavy and light chain CDR segments from particular SEQ ID NOs, and corresponding polynucleotides encoding the defined heavy- and light-chain variable regions, with additional dependent coverage for pharmaceutical excipient formulations, specified heavy-chain variable-region post-translational modifications, and implementation via expression vectors, transformed host cells, and culturing for production.
Stated Advantages
Preferential binding to patient-derived peritoneal disseminated cancer cells via a TSPAN8 epitope spanning amino-acid positions 126–155, with T131 essential.
Cytotoxicity in vitro of the anti-TSPAN8(16B11)-anti-CD3 bispecific “bottle-opener” antibody.
Anti-tumor activity in vivo with extended survival in peritoneal dissemination mouse models.
Documented Applications
Treating cancer by administering a therapeutically effective amount of an anti-TSPAN8 antibody or an antigen-binding fragment to a subject.
Use of the anti-TSPAN8(16B11)-anti-CD3 bispecific “bottle-opener” antibody for cytotoxic and anti-tumor effects against peritoneal disseminated cancer, consistent with redirected T cell cytotoxicity (RTCC).
Peritoneal dissemination mouse models for assessing anti-tumor activity and survival extension.
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