Selective drug release from internalized conjugates of biologically active compounds
The invention relates to conjugates of biologically active compounds, wherein such a conjugate is comprised of a sequence of amino acids containing a tripeptide that confers selective cleavage by tumor tissue homogenate for release of free drug and/or improves biodistribution into the tumor tissue in comparison to normal tissue homogenate from the same species, wherein the normal tissue is the site of an adverse event associated with administration to a human subject in need thereof of a therapeutically effective amount of a comparator conjugate whose amino acid sequence is a dipeptide known to be selectively cleavable by Cathepsin B.
1. An antibody-drug conjugate comprising an antigen binding protein or fragment thereof that binds CD30, wherein the antibody-drug conjugate is represented by the structure:
or a pharmaceutically acceptable salt thereof, wherein
Ab is the antigen binding protein or fragment thereof and p denotes a number from 1 to 12.
2. The antibody-drug conjugate of claim 1 wherein the antigen binding protein or fragment is cAC10.
3. The antibody-drug conjugate of claim 1 , wherein the antigen binding protein or fragment comprises the following 6 HVRs:
an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 920;
an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 921;
an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 922;
an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 923;
an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 924; and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 925.
4. The antibody-drug conjugate of claim 3 , wherein the antigen binding protein or fragment comprises a VH and a VL, wherein the VH has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 926 and the VL has at least 80%, 85%, 90%, 95% or 99% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 927.
5. The antibody-drug conjugate of claim 1 , wherein the antigen binding protein or fragment comprises a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 926 and the VL comprises the amino acid sequence of SEQ ID NO: 927.
6. The antibody-drug conjugate of claim 1 , wherein the antigen binding protein or fragment comprises an HC comprising the amino acid sequence of SEQ ID NO: 928 or SEQ ID NO: 929 and an LC comprising the amino acid sequence of SEQ ID NO: 930.
7. The antibody-drug conjugate of claim 1 , wherein the antigen binding protein or fragment is a monoclonal antibody or fragment thereof.
8. The antibody-drug conjugate of claim 1 , wherein the antigen binding protein or fragment is a chimeric antibody or fragment thereof.
9. The antibody-drug conjugate of claim 1 , wherein the antigen binding protein or fragment is a humanized antibody or fragment thereof.
10. The antibody-drug conjugate of claim 1 , wherein the fragment is selected from a Fab, Fab′, Fv, scFv or (Fab′) 2 fragment.
11. A pharmaceutical composition comprising the antibody-drug conjugate of claim 1 and a pharmaceutically acceptable carrier.
12. A method of treating a CD30-expressing disease or condition in an individual comprising administering to an individual in need thereof an effective amount of the antibody-drug conjugate of claim 1 .