Multispecific antibodies against CD40 and CD137
Inventors
Altintas, Isil • Satijn, David • RADEMAKER, Rik • Parren, Paul • Gieseke, Friederike • Sahin, Ugur
Assignees
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Publication Number
US-11939388-B2
Publication Date
2024-03-26
Expiration Date
Abstract
Multispecific antibodies binding to human CD40 and human CD137, methods for preparing such multispecific antibodies, and methods of using such multispecific antibodies for therapeutic or other purposes.
Core Innovation
The invention relates to a nucleic acid or a set of nucleic acids encoding a multispecific antibody that includes two binding arms. A first binding arm comprises a first antigen-binding region binding to human CD40, and a second binding arm comprises a second antigen-binding region binding to human CD137, with heavy and light chain variable region CDR1, CDR2, and CDR3 sequences set forth for each arm.
The multispecific antibody is further defined by variant criteria for framework identity relative to specified SEQ ID framework sequences and by allowable numbers of CDR mutations relative to specified CDR sequences. The document context also specifies particular VH/VL sequence choices for the CD137 arm, including humanized CD137 clone 009 and optional alternative clone 005 choices.
Structural and format context is provided for assembling the multispecific or bispecific antibody arms, including constant-region compositions, immunoglobulin framework regions FR1 through FR4, and downstream biological and functional context. The disclosed antibodies enable CD40×CD137 crosslinking and trans-activation of both receptors, including activation pathways associated with NF-κB.
Claims Coverage
The provided independent claim covers nucleic acids encoding a multispecific antibody with two distinct antigen-binding arms to human CD40 and human CD137. Across the dependent claims in the provided text, multiple inventive features refine the defined VH/VL variable regions, framework and variant criteria, and additional molecular elements and constraints for the encoded antibody format.
Two-arm multispecific antibody for human CD40 and human CD137
A nucleic acid or set of nucleic acids encoding a multispecific antibody comprising a first binding arm with an antigen-binding region binding to human CD40 and a second binding arm with an antigen-binding region binding to human CD137, with the recited VH and VL CDR1, CDR2, and CDR3 sequences for each arm.
Alternative SEQ ID–specified sequences for first binding region
The nucleic acid or set of nucleic acids of claim 1 such that the first antigen-binding region includes a VH with an amino acid sequence of SEQ ID NO:117 or SEQ ID NO:6.
Alternative SEQ ID–specified sequences for second binding region
The nucleic acid or set of nucleic acids of claim 1 such that the second antigen-binding region includes a VL sequence containing an amino acid sequence of SEQ ID NO:127 or SEQ ID NO:70.
Framework region structural composition defined by CDR1–CDR3 and FR1–FR4
The nucleic acid(s) encoding the antigen-binding regions include heavy-chain and light-chain variable sequences whose VH and VL each contain three CDRs and four framework regions for both a first and a second antigen-binding region.
Expression vector including the recited nucleic acids
An expression vector including the nucleic acid(s) recited in claim 1.
Positional constraint on amino-acid substitutions in two heavy chains
The nucleic acid or set of nucleic acids encoding two heavy chains where each heavy chain contains amino-acid substitutions at EU-numbered positions selected from T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain according to EU numbering, with the substitutions in the two heavy chains occurring in different positions.
Across the independent claim and its dependent refinements in the provided text, the claim set is focused on specific VH/VL CDR definitions for CD40 and CD137 binding arms, with additional dependent limitations introducing alternative SEQ ID–specified VH/VL sequences, specifying CDR and framework-region composition, and further narrowing the encoded construct via an expression vector and positional constraints on heavy-chain substitutions.
Stated Advantages
Induces anti-tumor immunity through CD40×CD137 crosslinking and trans-activation of both receptors.
Supports NF-κB activation in the context of CD40×CD137 engagement.
Induces T-cell proliferation.
Expands tumor-infiltrating lymphocytes (TILs) in cancer contexts.
Documented Applications
No documented applications found
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