Anti-human CSF-1R antibody and uses thereof
Inventors
Ho, Chen-Hsuan • Liao, Chu-Bin • Chen, Yu-Kai • Huang, Chen-Wei • YANG, Tze-Ping • LAI, SZU-LIANG
Assignees
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Publication Number
US-12043668-B2
Publication Date
2024-07-23
Expiration Date
Abstract
An antibody, or an antigen-binding fragment thereof, that binds specifically to human CSF-1R includes a heavy chain variable domain that contains a HCDR1 region having the sequence of SEQ ID NO: 4, a HCDR2 region having the sequence of SEQ ID NO: 5, and a HCDR3 region having the sequence of SEQ ID NO: 6; and a light chain variable domain that contains a LCDR1 region having the sequence of SEQ ID NO: 7, a LCDR2 region having the sequence of SEQ ID NO: 8, and a LCDR3 region having the sequence of SEQ ID NO: 9. The heavy chain variable domain comprises the sequence of SEQ ID NO: 2, and wherein the light chain variable domain comprises the sequence of SEQ ID NO: 3.
Core Innovation
The invention relates to an antibody, or an antigen-binding fragment thereof, that binds specifically to human CSF-1R. The antibody is defined by a heavy chain variable domain containing HCDR1, HCDR2, and HCDR3 regions having the sequences of SEQ ID NOs 4–6, and a light chain variable domain containing LCDR1, LCDR2, and LCDR3 regions having the sequences of SEQ ID NOs 7–9. In representative examples, the antibody AB21 binds human CSF-1R with high affinity and provides functional blockade of ligand binding.
The antibody targets an extracellular-domain epitope on human CSF-1R, mapped to residues 228–233. In the examples, epitope mapping identifies the epitope sequence as Ser-Val-Asp-Val-Asn-Phe (SEQ ID NO:17), and the antibody blocks CSF-1/CSF-1R interaction. The document reports inhibition of downstream signaling, including reduced CSF-1R phosphorylation and reduced AKT phosphorylation, consistent with functional interference with CSF-1R signaling.
The document further reports that the antibody suppresses CSF-1-dependent cell growth and includes in vivo evidence of tumor growth inhibition in an RKO colorectal cancer model. The disclosure also discusses potential combination with pembrolizumab (anti–PD-1) and frames therapeutic use for diseases mediated by CSF-1/CSF-1R/IL-34, including PVNS, osteoporosis, and inflammatory arthritis, as well as CSF-1R/CSF-1/IL-34–mediated cancers.
Claims Coverage
The independent claim set centers on human CSF-1R-binding antibodies defined by specific heavy- and light-chain CDR sequences. Dependent claims further refine the target epitope, add inhibition of CSF-1-induced and/or IL-34-induced signaling, and include ADCs and pharmaceutical compositions for selected cancers.
Human CSF-1R-specific antibody defined by HCDR1, HCDR2, and HCDR3 sequences
The antibody (or antigen-binding fragment) that binds specifically to human CSF-1R comprises a heavy chain variable domain with an HCDR1 region having the sequence of SEQ ID NO: 4, an HCDR2 region having the sequence of SEQ ID NO: 5, and an HCDR3 region having the sequence of SEQ ID NO: 6.
Human CSF-1R-specific antibody defined by LCDR1, LCDR2, and LCDR3 sequences
The antibody (or antigen-binding fragment) that binds specifically to human CSF-1R comprises a light chain variable domain with a LCDR1 region having the sequence of SEQ ID NO: 7, a LCDR2 region having the sequence of SEQ ID NO: 8, and a LCDR3 region having the sequence of SEQ ID NO: 9.
Variable domain sequence alternatives with homology constraint
The antibody (or antigen-binding fragment) has a heavy-chain variable domain matching a specified SEQ ID NO or having at least 95% homology to the specified sequence, and a light-chain variable domain matching a specified SEQ ID NO or having at least 95% homology to the specified sequence.
Extracellular-domain epitope specificity for CSF-1R
The antibody (or antigen-binding fragment) specifically binds an epitope in the extracellular domain of human CSF-1R, where the extracellular domain sequence is SEQ ID NO: 1 and the epitope sequence is Ser-Val-Asp-Val-Asn-Phe (SEQ ID NO: 17).
Inhibition of CSF-1-induced and/or IL-34-induced signaling
The antibody (or antigen-binding fragment) inhibits CSF-1-induced signaling and/or IL-34-induced signaling.
Antibody-drug conjugate format
The antibody (or antigen-binding fragment) further includes a drug conjugate covalently linked to form an antibody-drug conjugate (ADC).
Pharmaceutical composition for selected cancers
A pharmaceutical composition is defined for use against a cancer selected from the specified group of cancer types, including multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, giant cell tumor of bone, non-small-cell lung cancers, giant cell tumor of the tendon sheath, renal cancer, metastasis of tumors to other tissues, myelofibrosis, and gastrointestinal stromal tumor.
Overall, the claim coverage centers on human CSF-1R-binding antibodies defined by specific heavy- and light-chain CDR sequences, optionally extended by homology-based variable domain alternatives. The dependent claims further narrow binding to a defined extracellular-domain epitope, require inhibition of CSF-1-induced and/or IL-34-induced signaling, and include ADCs and pharmaceutical compositions for enumerated cancer types.
Stated Advantages
High affinity binding to CSF-1R is reported for an exemplar antibody (AB21).
The antibody blocks CSF-1/CSF-1R interaction.
The antibody inhibits downstream signaling, including reduced CSF-1R phosphorylation and reduced AKT phosphorylation.
The antibody suppresses CSF-1-dependent cell growth.
In vivo tumor growth inhibition is reported in an RKO colorectal cancer model.
Documented Applications
Therapeutic use for cancers and inflammatory/immunological diseases mediated by CSF-1R/CSF-1/IL-34, including PVNS, osteoporosis, and inflammatory arthritis.
Use in cancer contexts is described for multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, giant cell tumor of bone, non-small-cell lung cancer, giant cell tumor of the tendon sheath, renal cancer, myelofibrosis, and gastrointestinal stromal tumor.
Potential combination with pembrolizumab (anti–PD-1) is discussed.
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