Site-specific engineered cysteine antibody drug conjugates
AssigneeSeagen Inc.
InventorsJamie Apperson MITCHELL, Robert Patrick LYON
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Abstract
The present application provides compositions and methods relating to antibodies that comprise cysteine engineered residues for conjugating drug moieties, thereby forming antibody drug conjugates (ADCs). The present disclosure also provides methods for decreasing ADC toxicity. The antibodies and ADCs (e.g., cysteine engineered antibodies and cysteine engineered ADCs) are useful for treatment of various cancers.
Claims61
A cysteine engineered antibody comprising cysteine amino acid substitutions, wherein:
- i) the cysteine engineered antibody comprises a heavy chain and a light chain;
- and,
- ii) the cysteine amino acid substitutions are selected from the group consisting of:
- a) position 121 of the light chain and position 375 of the heavy chain;
- b) position 121 of the light chain and position 400 of the heavy chain;
- and
- c) position 114 of the light chain and position 400 of the heavy chain,
- wherein the amino acid position numbering in the light chain is according to Kabat numbering and the amino acid position numbering in the heavy chain is according to EU numbering.
A method of reducing toxicity of an ADC comprising an antibody moiety conjugated to a drug moiety, the method comprising:
- generating a cysteine engineered ADC comprising cysteine amino acid substitutions, wherein the cysteine engineered ADC comprises a cysteine engineered antibody comprising a heavy chain and a light chain, and wherein the cysteine amino acid substitutions are selected from the group consisting of:
- a) position 121 of the light chain and position 375 of the heavy chain;
- b) position 121 of the light chain and position 400 of the heavy chain;
- and,
- c) position 114 of the light chain and position 400 of the heavy chain,
- wherein the amino acid position numbering in the light chain is according to Kabat numbering and the amino acid position numbering in the heavy chain is according to EU numbering,
- wherein the drug moiety is conjugated to each of the cysteine amino acid substitutions, thereby reducing toxicity of the cysteine engineered ADC compared to a second cysteine engineered ADC that comprises a drug moiety conjugated to a cysteine amino acid at one or more other positions, when administered to a patient.
A method of reducing toxicity of a cysteine engineered ADC when administered to a patient, wherein the cysteine engineered ADC comprises a cysteine engineered antibody and a drug moiety, the method comprising:
- conjugating the drug moiety to a cysteine amino acid of the cysteine engineered antibody via a linker moiety, wherein the cysteine amino acid is at a position that reduces the stability of the cysteine engineered ADC compared to a second cysteine engineered ADC that comprises a drug moiety conjugated to a cysteine amino acid of a cysteine engineered antibody at one or more other positions.
Dependencies are inferred from the claim text.