Monoclonal antibodies specific for fibroblast growth factor receptor 4 (FGFR4) and methods of their use
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.
1. An isolated monoclonal antibody that specifically binds fibroblast growth factor receptor 4 (FGFR4), or an antigen-binding fragment thereof, comprising a variable heavy (VH) domain and a variable light (VL) domain, wherein:
the amino acid sequence of the VH domain of the antibody comprises the complementarity determining region 1 (CDR1), CDR2 and CDR3 sequences of SEQ ID NO: 3, wherein the CDR1, CDR2, and CDR3 sequences respectively comprise residues 26-33, 52-59, and 98-111 of SEQ ID NO:3; and
the amino acid sequence of the VL domain of the antibody comprises the CDR1, CDR2 and CDR3 sequences of SEQ ID NO: 4, wherein the CDR1, CDR2, and CDR3 sequences respectively comprise residues 27-32, 50-52, and 88-98 of SEQ ID NO:4.
2. The monoclonal antibody or antigen-binding fragment of claim 1 , wherein:
the amino acid sequence of the VH domain is at least 90% identical to SEQ ID NO: 3 and the amino acid sequence of the VL domain is at least 90% identical to SEQ ID NO: 4.
3. The monoclonal antibody or antigen-binding fragment of claim 1 , wherein:
the amino acid sequence of the VH domain comprises SEQ ID NO: 3 and the amino acid sequence of the VL domain comprises SEQ ID NO: 4.
4. The antigen-binding fragment of claim 1 , wherein the antigen-binding fragment is an Fab fragment, an Fab′ fragment, an F(ab)′ 2 fragment, a single chain variable fragment (scFv) or a disulfide stabilized variable fragment (dsFv).
5. The monoclonal antibody of claim 1 , wherein the antibody is an IgG.
6. The monoclonal antibody or antigen-binding fragment of claim 1 , which is a fully human antibody or antigen-binding fragment.
7. The monoclonal antibody or antigen-binding fragment of claim 1 , which is a chimeric, synthetic, or humanized antibody or antigen-binding fragment.
8. A composition comprising the monoclonal antibody or antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier.
9. The antigen-binding fragment of claim 4 , wherein the fragment is a scFv comprising the amino acid sequence of SEQ ID NO: 38.