Cysteine engineered anti-MUC16 antibodies and antibody drug conjugates
First Claim
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1. An isolated cysteine engineered anti-MUC16 antibody which binds to a MUC16 polypeptide comprising the heavy chain sequence of SEQ ID NO:
- 1.
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Abstract
Cysteine engineered anti-MUC16 antibodies are engineered by replacing one or more amino acids of a parent anti-MUC16 antibody with non cross-linked, reactive cysteine amino acids. Methods of design, preparation, screening, and selection of the cysteine engineered anti-MUC16 antibodies are provided. Cysteine engineered anti-MUC16 antibodies (Ab) are conjugated with one or more drug moieties (D) through a linker (L) to form cysteine engineered anti-MUC16 antibody-drug conjugates having Formula I:
Ab-(L-D)p I
- where p is 1 to 4. Diagnostic and therapeutic uses for cysteine engineered antibody drug compounds and compositions are disclosed.
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Citations
40 Claims
- 1. An isolated cysteine engineered anti-MUC16 antibody which binds to a MUC16 polypeptide comprising the heavy chain sequence of SEQ ID NO:
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8. A method of determining the presence of a MUC16 protein in a sample suspected of containing said protein, said method comprising the steps of:
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exposing said sample to the cysteine engineered anti-MUC16 antibody having the heavy chain sequence of SEQ ID NO;
1, and;determining binding of said antibody to said MUC16 protein in said sample, wherein binding of the antibody to said protein is indicative of the presence of said protein in said sample. - View Dependent Claims (9, 10)
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12. An antibody-drug conjugate comprising a cysteine engineered anti-MUC16 antibody (Ab) which binds to a MUC16 polypeptide and comprising the heavy chain sequence of SEQ ID NO:
- 1, and an auristatin drug moiety (D) wherein the cysteine engineered anti-MUC16 antibody is attached through a free cysteine amino acid by a linker moiety (L) to D;
the compound having Formula I;
Ab-(L-D)p
Iwhere p is 1, 2, 3, or 4. - View Dependent Claims (13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)
- 1, and an auristatin drug moiety (D) wherein the cysteine engineered anti-MUC16 antibody is attached through a free cysteine amino acid by a linker moiety (L) to D;
- 27. An antibody-drug conjugate compound selected from the structures:
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29. A mixture of antibody-drug conjugate compounds comprising a cysteine engineered anti-MUC16 antibody (Ab) which binds to a MUC16 polypeptide and comprising the heavy chain sequence of SEQ ID NO:
- 1, and an auristatin drug moiety (D) wherein the cysteine engineered anti-MUC16 antibody is attached through a free cysteine amino acid by a linker moiety (L) to D;
the compound having Formula I;
Ab-(L-D)p
Iwhere p is 1, 2, 3, or 4, and the average drug loading is from 1 to 2.
- 1, and an auristatin drug moiety (D) wherein the cysteine engineered anti-MUC16 antibody is attached through a free cysteine amino acid by a linker moiety (L) to D;
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30. A pharmaceutical formulation comprising an antibody-drug conjugate comprising a cysteine engineered anti-MUC16 antibody which binds to a MUC16 polypeptide and comprising the heavy chain sequence SEQ ID NO:
- 1 and where the cysteine engineered anti-MUC16 antibody is covalently attached through a free cysteine amino acid to an auristatin drug moiety, and a pharmaceutically acceptable diluent, carrier or excipient.
- View Dependent Claims (31)
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32. A method of treating cancer comprising administering to a patient a pharmaceutical formulation comprising an antibody-drug conjugate comprising a cysteine engineered anti-MUC16 antibody which binds to a MUC16 polypeptide and having the heavy chain sequence of SEQ ID NO:
- 1 and where the cysteine engineered anti-MUC16 antibody is covalently attached through a free cysteine amino acid to an auristatin drug moiety, and a pharmaceutically acceptable diluent, carrier or excipient; and
wherein the cancer is selected from the group consisting of ovarian cancer, prostate cancer, cancer of the urinary tract, pancreatic cancer, lung cancer, breast cancer, and colon cancer. - View Dependent Claims (33)
- 1 and where the cysteine engineered anti-MUC16 antibody is covalently attached through a free cysteine amino acid to an auristatin drug moiety, and a pharmaceutically acceptable diluent, carrier or excipient; and
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34. An article of manufacture comprising
a pharmaceutical formulation comprising an antibody-drug conjugate comprising a cysteine engineered anti-MUC16 antibody which binds to a MUC16 polypeptide and having the heavy chain sequence of SEQ ID NO: - 1 and where the cysteine engineered anti-MUC16 antibody is covalently attached through a free cysteine amino acid to an auristatin drug moiety, and a pharmaceutically acceptable diluent, carrier or excipient;
a container; and a package insert or label indicating that the compound can be used to treat ovarian cancer, prostate cancer, cancer of the urinary tract, pancreatic cancer, lung cancer, breast cancer, or colon cancer characterized by the overexpression of a MUC16 polypeptide.
- 1 and where the cysteine engineered anti-MUC16 antibody is covalently attached through a free cysteine amino acid to an auristatin drug moiety, and a pharmaceutically acceptable diluent, carrier or excipient;
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35. A method for making an antibody drug conjugate compound comprising a cysteine engineered anti-MUC16 antibody (Ab) which binds to a MUC16 polypeptide and having the heavy chain sequence of SEQ ID NO:
- 1, and an auristatin drug moiety (D) wherein the cysteine engineered antibody is attached through an engineered cysteine amino acid by a linker moiety (L) to D;
the compound having Formula I;
Ab-(L-D)p
Iwhere p is 1, 2, 3, or 4;
the method comprising the steps of;(a) reacting an engineered cysteine group of the cysteine engineered antibody with a linker reagent to form antibody-linker intermediate Ab-L; and (b) reacting Ab-L with an activated drug moiety D;
whereby the antibody-drug conjugate compound is formed;or comprising the steps of; (c) reacting a nucleophilic group of a drug moiety with a linker reagent to form drug-linker intermediate D-L; and (d) reacting D-L with an engineered cysteine group of the cysteine engineered antibody;
whereby the antibody-drug conjugate compound is formed. - View Dependent Claims (36, 37, 38, 39, 40)
- 1, and an auristatin drug moiety (D) wherein the cysteine engineered antibody is attached through an engineered cysteine amino acid by a linker moiety (L) to D;
Specification