Modified human IgM constant regions for modulation of complement-dependent cytolysis effector function
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Publication Number
US-11401337-B2
Publication Date
2022-08-02
Expiration Date
Abstract
The disclosure provides modified human IgM heavy chain constant regions that include one or more amino acid substitutions, e.g., in the Cμ3 domain, where a modified human IgM antibody comprising the modified IgM constant region and a heavy chain variable region specific for a target antigen exhibits reduced complement-dependent cytotoxicity (CDC) of cells expressing the target antigen relative to a corresponding wild-type human IgM antibody.
Core Innovation
The disclosure describes modified human IgM heavy-chain constant regions comprising one or more amino acid substitutions relative to a wild-type human IgM constant region. At least one substitution is located in the Cμ3 domain at positions L310, P311, P313, or K315 of SEQ ID NO: 1, including combinations of substitutions. The modified IgM antibody is configured to bind a target antigen via a heavy chain variable region specific for the target antigen.
A modified IgM antibody comprising the modified IgM constant region exhibits reduced complement-dependent cytotoxicity (CDC) of cells expressing the target antigen relative to a corresponding wild-type human IgM antibody that is otherwise identical except for the modification. The disclosure characterizes reductions in CDC activity, including maximum CDC activity in a dose-response assay and changes in complement-mediated lysis potency as reflected by EC50.
The disclosure also describes IgM antibody formats and assemblies, including pentameric or hexameric IgM antibodies with a J-chain or an engineered modified J-chain. In bispecific IgM constructs with an engineered modified J-chain binding CD3ε, the disclosed modifications preserve T-cell activation and killing potency while reducing/eliminating CDC, including examples such as double mutants.
Claims Coverage
The document provides one independent claim covering the modified human IgM constant region and the resulting reduction of CDC, with dependent claims refining specific residue substitutions, quantitative CDC constraints, and IgM format and J-chain engineering. The independent claim includes a minimum inventive requirement of placing at least one specified Cμ3-domain substitution (L310, P311, P313, or K315) in SEQ ID NO: 1 and demonstrating reduced CDC relative to a corresponding wild-type IgM.
Cμ3-domain substitutions in modified IgM constant region
A modified human IgM constant region comprises one or more amino acid substitutions relative to a wild-type human IgM constant region, wherein at least one amino acid substitution is in the Cμ3 domain at position L310, position P311, position P313, position K315 of SEQ ID NO: 1, or a combination thereof.
Reduced CDC by target-specific modified IgM relative to wild-type
A modified IgM antibody comprising the modified IgM constant region and a heavy chain variable region specific for a target antigen exhibits reduced complement-dependent cytotoxicity (CDC) of cells expressing the target antigen relative to a corresponding wild-type human IgM antibody identical except for the modified human IgM.
Overall, claim coverage centers on constant-region engineering in the Cμ3 domain at L310, P311, P313, and/or K315 (SEQ ID NO: 1) to produce target-specific IgM antibodies that reduce complement-dependent cytotoxicity compared with otherwise-identical wild-type IgM.
Stated Advantages
Reduced complement-dependent cytotoxicity (CDC) of target antigen-expressing cells relative to a corresponding wild-type human IgM antibody.
Reduced maximum CDC activity in a dose-response assay versus the corresponding wild-type human IgM antibody.
Preservation of T-cell activation and killing potency in bispecific IgM constructs despite elimination/reduction of CDC (double mutants described).
Documented Applications
Use in bispecific IgM constructs including an engineered modified J-chain binding CD3ε to preserve T-cell activation and killing potency while eliminating/reducing CDC.
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