Conditionally active anti-EpCAM antibodies, antibody fragments, their immunoconjugates and uses thereof
Inventors
Short, Jay M. • Frey, Gerhard • Chang, Hwai Wen
Assignees
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Publication Number
US-12427347-B2
Publication Date
2025-09-30
Expiration Date
Abstract
Isolated polypeptides having a heavy chain variable region and/or light chain variable region that specifically binds to EpCAM protein as well as antibodies and antibody fragments containing the heavy chain variable region and/or the light chain variable region that bind to EpCAM protein. Pharmaceutical compositions and kits comprising the polypeptide and antibodies and antibody fragments containing the polypeptide are also provided.
Core Innovation
The invention provides a method of treating cancer by administering to a patient an antibody or antibody fragment that specifically binds to human EpCAM protein. The antibody or antibody fragment includes a heavy chain variable region and a light chain variable region with complementarity determining regions H1, H2, H3, L1, L2, and L3, with defined sequence constraints and a proviso restricting simultaneous substitutions.
The heavy chain variable region sequences include H1 as GYTFTSYWMH, H2 as X1IRPSTGYTEYNQKFKD, and H3 as GDNWVGFAN, where X1 is Y or D. The light chain variable region sequences include L1 as SASSSISYMH, L2 as STSNLX2S with X2 being A or H, and L3 as X3QWSTYX4T with X3 being H or E and X4 being H or E.
The invention addresses limitations of prior anti-EpCAM therapy by using EpCAM-binding antibodies with conditional or conditionally active binding characteristics. The conditional binding is associated with tumor microenvironment conditions, with reduced binding activity at non-tumor microenvironment conditions and retained binding activity under acidic tumor microenvironment conditions.
Claims Coverage
The provided independent claim set centers on a method of treating cancer by administering a therapeutically effective amount of an EpCAM-specific antibody or antibody fragment having defined VH and VL complementarity determining region sequences. Across the independent claim(s) provided, the primary inventive coverage consists of EpCAM-specific binding antibodies with constrained H1, H2, H3, L1, L2, and L3 sequence patterns, combined with treatment administration to a patient.
EpCAM-specific antibody variable region CDR sequence constraints
An antibody or antibody fragment that specifically binds human EpCAM, the antibody comprising a heavy chain variable region and a light chain variable region, where the heavy chain variable region includes three complementarity determining regions having sequences H1, H2, and H3, and the light chain variable region includes three complementarity determining regions having sequences L1, L2, and L3, with the stated residue constraints and a proviso that the specified substitutions cannot simultaneously occur.
Therapeutically effective administration to treat cancer
A method of treating cancer comprising administering to a patient having cancer a therapeutically effective amount of the specified EpCAM-binding antibody or antibody fragment.
EpCAM-binding antibody variable regions with constrained CDR sequences
Administering to a patient having cancer a therapeutically effective amount of an antibody or antibody fragment that specifically binds to human EpCAM protein, wherein the heavy chain variable region includes three complementarity determining regions with sequences H1, H2, and H3, and the light chain variable region includes three complementarity determining regions with sequences L1, L2, and L3, with the specified sequence constraints and the proviso that X1, X2, X3 and X4 cannot be Y, A, H, and H at the same time.
Treating cancer with heavy- and light-chain CDR sequences using defined substitutions
The heavy chain variable region includes H1 as GYTFTSYWMH, H2 as X1IRPSTGYTEYNQKFKD with X1 being Y or D, and H3 as GDNWVGFAN, and the light chain variable region includes L1 as SASSSISYMH, L2 as STSNLX2S with X2 being A or H, and L3 as X3QWSTYX4T with X3 being H or E and X4 being H or E.
The claim coverage provided is anchored in EpCAM-specific antibodies whose VH and VL each contain three CDRs with specified sequence constraints and substitution restrictions, used in a therapeutically effective administration to treat cancer. The independent claim content also recites the specific CDR sequences and variable-residue options, including a prohibition on a specific combination of X1–X4 values.
Stated Advantages
The invention addresses limitations of prior anti-EpCAM therapy.
Conditional binding is associated with reduced binding activity at non-tumor microenvironment conditions and retained binding activity under acidic tumor microenvironment conditions.
Documented Applications
Treatment of cancer.
Diagnostic and prognostic detection of EpCAM.
Antibody-drug conjugates and other immunoconjugates.
Combination contexts with immune checkpoint inhibitors and other antibody agents.
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