Monoclonal antibodies specific for fibroblast growth factor receptor 4 (FGFR4) and methods of their use
Inventors
Khan, Javed • Baskar, Sivasubramanian • Orentas, Rimas J. • Dimitrov, Dimiter S. • Zhu, Zhongyu • Cheuk, Tai Chi
Assignees
US Department of Health and Human Services
Publication Number
US-11078286-B2
Publication Date
2021-08-03
Expiration Date
2036-09-19
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Abstract
Monoclonal antibodies selected from immunized mice, immunized rabbits and a human scFv library that specifically bind fibroblast growth factor receptor 4 (FGFR4) are described. Chimeric antigen receptors, antibody-drug conjugates, immunoconjugates, bispecific antibodies and immunoliposomes comprising the disclosed FGFR4-specific antibodies are also described. The antibody compositions can be used to diagnose or treat a FGFR4-positive cancer, such as rhabdomyosarcoma, lung cancer, liver cancer, breast cancer, pancreatic cancer or prostate cancer.
Core Innovation
The invention provides monoclonal antibodies, including antigen-binding fragments thereof, that specifically bind fibroblast growth factor receptor 4 (FGFR4). These antibodies were selected from mice and rabbits immunized with the extracellular domain of human FGFR4, and from a human single-chain variable fragment (scFv) library. The invention also covers chimeric antigen receptors (CARs), antibody-drug conjugates (ADCs), immunoconjugates, bispecific antibodies, immunoliposomes, and compositions comprising the disclosed FGFR4-specific antibodies.
The antibodies and their compositions can be used in methods for diagnosing or treating FGFR4-positive cancers, including rhabdomyosarcoma (both alveolar and embryonal subtypes), lung cancer, liver cancer, breast cancer, pancreatic cancer, and prostate cancer. Monoclonal antibodies comprising specific heavy and light chain variable domain complementarity determining regions (CDRs) selected from disclosed mouse, rabbit, and human antibodies are provided. Moreover, nucleic acid molecules and vectors encoding the FGFR4-specific antibodies and related constructs are included.
The problem addressed arises from the poor prognosis and therapeutic challenges associated with FGFR4-positive cancers, particularly rhabdomyosarcoma (RMS), which is the most common soft tissue sarcoma of childhood. Although relapse-free survival rates have improved with current treatments, metastatic disease survival remains low. FGFR4 is a known metastatic regulator, overexpressed and mutationally activated in RMS and other cancers, and is associated with aggressive tumor phenotypes and poor survival. Thus, there is a need to develop specific therapeutic agents targeting FGFR4 to inhibit tumor growth and metastasis effectively.
Claims Coverage
The patent includes one independent claim defining a monoclonal antibody specifically binding FGFR4 with defined variable heavy and light chain domains. The main inventive features relate to the specific complementarity determining region (CDR) sequences of the antibody and its binding specificity.
Monoclonal antibody with specific FGFR4 binding CDR sequences
An isolated monoclonal antibody or antigen-binding fragment thereof comprising a variable heavy (VH) domain and a variable light (VL) domain, wherein the VH domain comprises CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 3 (residues 26-33, 52-59, and 98-111) and the VL domain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 4 (residues 27-32, 50-52, and 88-98). This antibody specifically binds FGFR4.
Antibody sequence identity and form
The antibody VH and VL domains have at least 90% sequence identity to SEQ ID NO: 3 and SEQ ID NO: 4 respectively, with specific embodiments including the exact sequences of SEQ ID NO: 3 and SEQ ID NO: 4. The antigen-binding fragment can be an Fab, Fab′, F(ab)′2, single chain variable fragment (scFv), or disulfide stabilized variable fragment (dsFv). The antibody is an IgG and can be fully human, chimeric, synthetic or humanized.
Pharmaceutical composition
Compositions comprising the monoclonal antibody or antigen-binding fragment of the disclosed antibody and a pharmaceutically acceptable carrier.
The claims cover isolated monoclonal antibodies specific for FGFR4 defined by particular CDR sequences, their antigen-binding fragments, forms, sequence identities, and pharmaceutical compositions including these antibodies.
Stated Advantages
The antibodies exhibit high specificity and affinity for FGFR4, allowing targeted binding to FGFR4-expressing tumor cells.
Cell-surface FGFR4 facilitates rapid internalization of bound antibodies, enabling the development of antibody-drug conjugates and CAR T-cell therapies that can effectively target and kill FGFR4-positive cancer cells.
The disclosed antibodies and antibody compositions enable diagnosis and treatment of FGFR4-positive cancers with potential improved therapeutic outcomes, especially in cancers with poor prognosis like metastatic rhabdomyosarcoma.
Documented Applications
Diagnosis of FGFR4-positive cancers by detecting FGFR4 expression in biological samples using the disclosed antibodies or antigen-binding fragments.
Treatment of FGFR4-positive cancers, including rhabdomyosarcoma (alveolar and embryonal subtypes), lung cancer, liver cancer, breast cancer, pancreatic cancer, and prostate cancer, using therapies comprising the disclosed monoclonal antibodies, antigen-binding fragments, ADCs, CARs, immunoconjugates, bispecific antibodies, or immunoliposomes.
Use of CAR T-cells expressing FGFR4-specific antigen-binding fragments to induce cytotoxicity against FGFR4-expressing tumor cells.
Development of antibody-drug conjugates that deliver cytotoxic agents specifically to FGFR4-expressing cancer cells to inhibit tumor growth and metastasis.
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