Anti-CTLA4 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-11542332-B2
Publication Date
2023-01-03
Expiration Date
Abstract
A polypeptide having a heavy chain variable region and/or light chain variable region that specifically binds to CTLA4 protein as well as antibodies and antibody fragments containing the heavy chain variable region and/or the light chain variable region that bind to CTLA4 protein. Pharmaceutical compositions and kits comprising the polypeptide or antibodies and antibody fragments containing the polypeptide are also provided.
Core Innovation
The invention provides an isolated polypeptide that specifically binds to the CTLA4 protein. The polypeptide comprises a heavy chain variable region with three complementarity determining regions (H1, H2, H3) and a light chain variable region with three complementarity determining regions (L1, L2, L3). H1, H2, and H3 are defined by specific sequences and position-dependent allowed substitutions, and L1, L2, and L3 are likewise defined by specific sequences and allowed substitutions.
The core construct is structured around the heavy chain variable region and the light chain variable region defined by CDR sequence rules. In particular, the H1 sequence is fixed as GFTFSHYTMH (SEQ ID NO: 1), while H2 and H3 are defined using specified motifs together with explicit constraints on the allowed amino acids at designated positions (X1–X8). The light chain CDRs include fixed sequences for L1–L3 (SEQ ID NO: 4–6) with constraints on allowed amino acids at designated positions (X9–X12).
The disclosed scope extends to anti-CTLA4 antibodies or antibody fragments derived from the polypeptide variable regions, and further to immunoconjugates and pharmaceutical compositions. The claims refine binding behavior using tumor microenvironment pH versus non-tumor microenvironment pH, including explicit pH ranges and binding-affinity selectivity ratios based on pH. The immunoconjugate scope includes at least one selected agent comprising a chemotherapeutic agent, a radioactive atom, a cytostatic agent, or a cytotoxic agent.
Claims Coverage
The identified claims center on an isolated CTLA4-binding polypeptide defined by heavy-chain and light-chain variable region CDR sequence rules. Dependent claims further refine antibody, immunoconjugate, and pharmaceutical composition scope and add pH-dependent binding selectivity constraints, as well as payload agent categories.
CTLA4-binding isolated polypeptide with defined heavy- and light-chain CDRs
An isolated polypeptide that specifically binds to CTLA4 protein, comprising a heavy chain variable region with three complementarity determining regions (H1, H2, H3) defined by specified sequences and allowed substitutions, and a light chain variable region with three complementarity determining regions (L1, L2, L3) defined by specified sequences and allowed substitutions.
Tumor versus non-tumor pH-dependent binding with defined affinity selectivity
An antibody or antibody fragment with binding-affinity selectivity for CTLA4 based on pH, requiring explicit tumor microenvironment and non-tumor microenvironment pH ranges and at least about a 1.5:1 ratio between binding affinities.
Immunoconjugate including at least one payload agent class
An immunoconjugate including at least one selected agent comprising a chemotherapeutic agent, a radioactive atom, a cytostatic agent, or a cytotoxic agent.
The claims are directed to a specifically CTLA4-binding isolated polypeptide defined by heavy- and light-chain CDR sequence constraints, with dependent refinements extending to pH-dependent CTLA4 binding selectivity in tumor versus non-tumor microenvironments and to immunoconjugates that include specific payload agent categories.
Stated Advantages
Reduced side effects via pH-dependent binding affinity selectivity between tumor microenvironment and non-tumor microenvironment.
Documented Applications
CTLA4-targeted immunoconjugates, including antibody-drug conjugates (ADCs) and conjugates comprising agents such as chemotherapeutic agents, cytostatic/cytotoxic agents, or radioactive atoms.
Pharmaceutical compositions and kits for administering the CTLA4-binding polypeptides/antibodies and related immunoconjugates.
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