Methionine containing antibodies for conjugation of agents
AssigneeThe Regents of the University of California
InventorsJames Wells, Hai Tran, Susanna Elledge
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Abstract
Provided herein are novel antibody-agent conjugates formed by the introduction of methionine residues to antibody scaffold light or heavy chains at select positions, followed by conjugation of the agent to the methionine, for example, by oxaziridine chemistries. Methionine substitutions at the targeted positions enable highly efficient functionalization to form very stable conjugates, including conjugates suitable for in vivo use. The positions were identified for the trastuzumab and other related scaffolds which can be engineered for affinity to any target antigen. The conjugates include ADCs and detections agents. Also disclosed are novel oxaziridine reagents for conjugation to methionines in proteins.
Claims21
An antigen-binding composition comprising an antibody scaffold;
- wherein the antibody scaffold comprises complementarity determining region sequences (CDRs) set forth in SEQ ID NOs:
- 2-4 and 6-8, with the provision that the methionine of SEQ ID NO:
- 8 is substituted with leucine;
- wherein the antibody scaffold comprises one or more introduced methionine residues present at a site in the antibody scaffold corresponding to LC066, LC074, and/or HC262;
- and
- wherein a functional molecule is conjugated to each of the one or more introduced methionine residues.
A method of functionalizing a polypeptide comprising one or more methionine residues with a selected composition, comprising the steps of
- reacting the polypeptide with an oxaziridine composition comprising an oxaziridine selected from the group consisting of,
- under suitable conditions for the formation of an intermediate composition comprising a sulfimide bond by the sulfur atom of the one or more introduced methionines;
- and
- performing a second reaction between the intermediate composition and the selected composition under suitable conditions for azide-alkyne reaction, wherein the selected composition comprises an alkyne group, thereby conjugating the selected composition to the polypeptide by sulfimide linkage.
A reagent for oxaziridine-mediated conjugation of molecules, comprising
Dependencies are inferred from the claim text.