PSMA-STEAP1 DUAL VARIABLE DOMAIN IMMUNOGLOBULIN (DVD-Ig) MOLECULES AND DRUG CONJUGATES
AssigneeAbbVie Inc.
InventorsEdward Han, Andrew C. Phillips, Regina M. Reilly, Debra Touw, Zhihong Liu
Life of this patent
Estimating the term…
Abstract
The present disclosure provides dual variable domain immunoglobulin (DVD-Ig) molecules that bind to human STEAP1 and human PSMA and their drug conjugates, and methods of using the same.
Claims19
A dual-variable domain immunoglobulin (DVD-Ig) drug conjugate comprising the following structure:
- wherein n is 1 or 2,
- wherein the DVD-Ig binds human STEAP1 and human PSMA,
- wherein the DVD-Ig comprises two identical heavy chains and two identical light chains,
- wherein each heavy chain comprises:
- a) a first heavy chain variable domain (VH1) comprising VH1-CDR1 (SEQ ID NO:
- 3), VH1-CDR2 (SEQ ID NO:
- 4), and VH1-CDR3 (SEQ ID NO:
- 5);
- b) a second heavy chain variable domain (VH2) comprising VH2-CDR1 (SEQ ID NO:
- 8), VH2-CDR2 (SEQ ID NO:
- 9), and VH2-CDR3 (SEQ ID NO:
- 10);
- and
- c) an IgG1 heavy chain constant region (CH1CH2CH3);
- wherein the VH1 and the VH2 are connected via a first peptide linker (L1), and each heavy chain is in the form of VH1-L1-VH2-CH1CH2CH3;
- wherein each light chain comprises:
- a) a first light chain variable domain (VL1) comprising VL1-CDR1 (SEQ ID NO:
- 13), VL1-CDR2 (SEQ ID NO:
- 14), and VL1-CDR3 (SEQ ID NO:
- 15);
- b) a second light chain variable domain (VL2) comprising VL2-CDR1 (SEQ ID NO:
- 18), VL2-CDR2 (SEQ ID NO:
- 19), and VL2-CDR3 (SEQ ID NO:
- 20), and
- c) a kappa light chain constant region (Cκ);
- wherein the VL1 and the VL2 are connected via a second peptide linker (L2), and each light chain is in the form of VL1-L2-VL2-CK;
- and
- wherein the first and the second heavy chains form a dimeric Fc region.
A dual-variable domain immunoglobulin (DVD-Ig) drug conjugate comprising the following structure:
- wherein n is 2, and wherein the DVD-Ig binds human STEAP1 and human PSMA, and comprises two identical heavy chains and two identical light chains,
- wherein each of the heavy chains comprise the amino acid sequence of SEQ ID NO:
- 1 or 24;
- and
- wherein each light chain comprises the amino acid sequence of SEQ ID NO:
- 11;
- wherein the first heavy chain and the second heavy chain are connected by two disulfide bridges, and wherein the two disulfide bridges are between the cysteine in position 226 of the first heavy chain and the cysteine in position 226 of the second heavy chain, and between the cysteine in position 229 of the first heavy chain and the cysteine in position 229 of the second heavy chain according to EU numbering;
- and
- wherein the Top1i linker-Drugs are conjugated to the cysteines at position C220 of the first and the second heavy chains of the DVD-Ig according to EU numbering.
A dual-variable domain immunoglobulin (DVD-Ig) drug conjugate comprising the following structure:
- wherein n is 2, and wherein the DVD-Ig binds human STEAP1 and human PSMA, and comprises two identical heavy chains and two identical light chains.
A pharmaceutical composition comprising a dual-variable domain immunoglobulin (DVD-Ig) drug conjugate comprising the following structure:
- wherein n is 2, and wherein the DVD-Ig binds human STEAP1 and human PSMA, and comprises two identical heavy chains and two identical light chains;
- wherein each of the heavy chains comprise the amino acid sequence of SEQ ID NO:
- 1 or 24;
- and
- wherein each light chain comprises the amino acid sequence of SEQ ID NO:
- 11.
A method of making a pharmaceutical composition, comprising mixing:
- a. a dual-variable domain immunoglobulin (DVD-Ig) drug conjugate comprising the following structure:
- wherein n is 2, and wherein the DVD-Ig binds human STEAP1 and human PSMA, and comprises two identical heavy chains and two identical light chains, wherein each of the heavy chains comprise the amino acid sequence of SEQ ID NO:
- 1 or 24, and wherein each light chain comprises the amino acid sequence of SEQ ID NO:
- 11;
- and
- b. a pharmaceutically acceptable carrier.
A nucleic acid encoding a heavy chain comprising the amino acid sequence shown as SEQ ID NO:
- 1 or 24, and/or a light chain comprising the amino acid sequence shown as SEQ ID NO:
- 11.
A composition comprising:
- a. a reduced DVD-Ig comprising two identical heavy chains comprising the amino acid sequence shown as SEQ ID NO:
- 1 or 24, and two identical light chains comprising the amino acid sequence shown as SEQ ID NO:
- 11;
- and
- b. a linker drug of formula (V):
A process for making a dual-variable domain immunoglobulin (DVD-Ig) drug conjugate of the following structure:
- wherein n is 2, and wherein the DVD-Ig binds human STEAP1 and human PSMA and comprises two identical heavy chains and two identical light chains, wherein each of the heavy chains comprise the amino acid sequence of SEQ ID NO:
- 1 or 24, and wherein each light chain comprises the amino acid sequence of SEQ ID NO:
- 11, comprising the steps of:
- a. reducing with a reducing agent a plurality of DVD-Igs comprising two identical heavy chains comprising the amino acid shown as SEQ ID NO:
- 1 or 24, and two identical light chains comprising the amino acid sequence shown as SEQ ID NO:
- 11;
- and
- b. conjugating the plurality of reduced DVD-Ig molecules with an excess of a linker drug of formula (V):
Dependencies are inferred from the claim text.