Anti-CD73 antibodies and use thereof
Inventors
Lee, Chun-Chung • LO, Yu-Hsun • Liao, Chu-Bin • HONG, Chen-Jei • CHEN, Sih-Yu • Wu, Yen-Yu • LAI, SZU-LIANG • Hu, Chih-Yung • Ke, Wen-Bin • JUAN, Ya-Ting • HUANG, Kao-Jean
Assignees
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Publication Number
US-12187806-B2
Publication Date
2025-01-07
Expiration Date
Abstract
The present invention relates to a novel antibody, an antigen-binding fragment thereof and the uses of the antibody and fragment, wherein the antibody and the fragment comprise specific complementarity-determining regions (CDRs) and/or specifically bind to human CD73 at specific epitopes.
Core Innovation
The invention relates to anti-human CD73 antibodies and antigen-binding fragments that bind to CD73 on at least one of the glutamic acid residue at position 296 and the arginine residue at position 297. The antibodies are defined by specific heavy chain variable domain CDR sequences and specific light chain variable domain CDR sequences, where the LCDR3 region includes a limited substitution option at a defined position.
The disclosed antibody program includes variants with defined VH/VL options and multiple antibody formats, including antibody or antigen-binding fragment formats, and further refinements toward engineered constructs. The variable-domain definitions specify heavy chain variable domain sequence options together with defined LCDR1 and LCDR2 sequences and LCDR3 sequences allowing a defined substitution set.
The invention positions the antibodies as inhibitors of CD73 activity in a context where CD73 is implicated in cancer and immune suppression pathways. The disclosure further provides epitope mapping and species specificity concepts, describing that binding and inhibition depend on CD73 E296/R297, and supports these findings using domain swapping, targeted point mutations, and structural modeling identifying CDR residues.
Claims Coverage
The document contains two independent claims that cover anti-CD73 antibodies or antigen-binding fragments defined by specific heavy- and light-chain variable domain CDR sequences, with CD73 binding linked to glutamic acid 296 and arginine 297. The coverage is organized around two inventive feature groups.
CD73-binding antibody with defined heavy-chain CDR sequences and CD73 E296/R297 involvement
An antibody or antigen-binding fragment comprising a heavy chain variable domain with HCDR1 comprising SEQ ID NO: 4, HCDR2 comprising SEQ ID NO: 5, and HCDR3 comprising SEQ ID NO: 6, and binding to CD73 on at least one of the glutamic acid residue at position 296 and the arginine residue at position 297.
CD73-binding antibody with defined light-chain CDR sequences and LCDR3 substitution set
An antibody or antigen-binding fragment comprising a light chain variable domain with LCDR1 comprising SEQ ID NO: 7, LCDR2 comprising SEQ ID NO: 8, and LCDR3 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with substitution of leucine residue at position 8 by methionine, glycine, histidine, arginine, glutamine or isoleucine, wherein the antibody binds to CD73 on at least one of the glutamic acid residue at position 296 and the arginine residue at position 297.
CD73-binding antibody with heavy-chain variable domain selected from specified SEQ ID NO options
An antibody or antigen-binding fragment comprising a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 29 to SEQ ID NO: 38, and binding to CD73 on at least one of the glutamic acid residue at position 296 and the arginine residue at position 297.
Collectively, the independent claims cover anti-CD73 antibodies and antigen-binding fragments that are defined by specific variable-domain CDR sequence content and that bind CD73 in a manner involving CD73 glutamic acid 296 and arginine 297. The second independent claim broadens the heavy-chain variable domain by allowing selection from specified SEQ ID NO options while maintaining the same defined light-chain LCDR1/LCDR2 sequences and an LCDR3 substitution option.
Stated Advantages
Superior and longer-lasting inhibition of AMP consumption versus Oleclumab.
Improved reversal of AMP-mediated T-cell proliferation suppression.
In vivo reduction of in situ CD73 activity with tumor growth inhibition described as dose-dependent.
Documented Applications
Inhibiting CD73 using a pharmaceutical composition comprising the claimed antibody or antigen-binding fragment.
Treating selected cancers using a pharmaceutical composition, with cancer types listed to include breast cancer, gastric cancer, colorectal cancer, gallbladder cancer, prostate cancer, ovarian carcinoma, chronic or acute lymphocytic leukemia, bladder cancer, brain tumor, kidney carcinoma, head and neck squamous cell carcinoma, glioblastoma, esophageal cancer, pancreatic cancer, renal carcinoma, oral cancer, lung cancer, colon adenocarcinoma, melanoma, and lymphoma.
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