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-11851499-B2
Publication Date
2023-12-26
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 isolated polypeptides and antibodies that specifically bind human EpCAM protein (CD326). The binding polypeptides include a heavy chain variable region and a light chain variable region, each comprising three complementarity determining regions, with fixed sequences and variable positions constrained by allowable amino-acid character sets and a proviso that prevents certain simultaneous substitutions.
The disclosure further defines antibody or antibody fragment variants by constraints on heavy chain variable region and light chain variable region combinations. The six complementarity determining regions are required to be identical to specified SEQ ID NO complementarity determining region sequences, and additional limitations include VH and VL sequence identity to particular SEQ ID NO amino acid sequences and enumerated VH/VL pairings.
The subject matter further provides conditionally active antibodies and fragments with higher binding and antigen activity at tumor microenvironment conditions than at non-tumor physiological pH conditions. The invention is extended to immunoconjugates, including ADCs, and related pharmaceutical compositions, kits, and diagnostic and therapeutic uses.
Claims Coverage
The independent claims cover EpCAM-binding isolated polypeptides and EpCAM-binding antibodies or antibody fragments defined by complementarity determining region sequence constraints, a residue-position proviso, and VH/VL pairing constraints defined by SEQ ID NO identity thresholds and enumerated pair options. Across the claims, the coverage focuses on three inventive features.
EpCAM-binding isolated polypeptides with constrained VH/VL CDR sequences
Isolated polypeptides comprising a heavy chain variable region and a light chain variable region that specifically bind to human EpCAM, 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 proviso that specified variable positions cannot occur simultaneously.
EpCAM-binding antibody or antibody fragment with defined VH/VL CDR sequences and proviso
An antibody or antibody fragment that specifically binds to human EpCAM protein comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes complementarity determining regions H1, H2, and H3 and the light chain variable region includes complementarity determining regions L1, L2, and L3, with the proviso that the specified variable positions cannot occur simultaneously.
EpCAM-binding antibody or antibody fragment defined by enumerated VH/VL identity pairings
An antibody or antibody fragment comprising a heavy chain variable region and a light chain variable region of a selected VH/VL pair, wherein the pair is selected from multiple alternatives having VH with at least 90% identity to specified SEQ ID NO amino acid sequences and VL with at least 90% sequence identity to specified SEQ ID NO amino acid sequences, the six complementarity determining regions being identical to the selected SEQ ID NO complementarity determining region sequences, and the antibody or antibody fragment specifically binds to human EpCAM protein.
The claim set is centered on EpCAM-specific binding polypeptides, antibodies, and antibody fragments defined by fixed complementarity determining region sequences, controlled residue options with a specific proviso, and additional VH/VL identity and pairing limitations.
Stated Advantages
Higher binding and antigen activity at tumor microenvironment conditions (acidic pH 6.0–6.8) than at non-tumor physiological pH conditions (about 7.0–7.6).
Activity retention drop at pH 7.4 versus pH 6.0 is quantified.
Documented Applications
Immunoconjugates including ADCs for use with the conditionally active antibodies.
Pharmaceutical compositions.
Kits.
Diagnostic uses and therapeutic uses.
Xenograft tumor treatment.
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