Tumor-specific payload delivery and immune activation using a human antibody targeting a highly specific tumor cell surface antigen
This invention provides antibodies directed against a highly specific and previously unrecognized marker for cancerous cells. In certain embodiments an isolated antibody or fragment thereof that specifically binds human placentally expressed ALPP and/or ALPPL2, but not ALPL and ALPI that are expressed outside the placenta is provided as well as immunoconjugates comprising such antibodies.
1. An isolated antibody that binds human placentally expressed ALPP and/or ALPPL2, but not ALPL and ALPI that are expressed outside the placenta wherein:
said antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), where:
said heavy chain variable region comprises a variable heavy M25FYIA antibody CDR1 comprising the amino acid sequence GFTFSSYA (residues 26-33 of SEQ ID NO:6), a variable heavy M25FYIA antibody CDR2 comprising the amino acid sequence ISYDGSNK (residues 51-58 of SEQ ID NO:6, and a variable heavy M25FYIA antibody CDR3 comprising the amino acid sequence AKEGDSSRWSYDL (residues 97-109 of SEQ ID NO:6); and
said light chain variable region comprises a variable light M25FYIA antibody CDR1 comprising the amino acid sequence SSDVGGYNY (residues 161-169 of SEQ ID NO:6), a variable light M25FYIA antibody CDR2 comprising the amino acid sequence DVT (residues 187-189 of SEQ ID NO:6), and a variable light M25FYIA antibody CDR3 consisting of the amino acid sequence SSYTIASTLVV (residues 226-236 of SEQ ID NO:6).
2. The antibody of claim 1 , wherein said antibody preferentially binds the cell surface form of ALPPL2 as compared to the shed form of ALPPL2.
3. The antibody of claim 1 , wherein:
said antibody binds a cell expressing ALPPL2 with an affinity of better than about 5 nM; and/or
said antibody binds a cell expressing ALPPL2 with an affinity of better than about 50 pM in its IgG1 form.
4. The antibody of claim 1 , wherein:
said antibody comprises a heavy chain variable region (VH) of an M25FYIA antibody comprising the amino acid sequence QVQLQQSGGGLVKPGGSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISYDGSN KYYADSVKGRFTISRDNSKNTLYLQMDSLRAEDTAVYYCAKEGDSSRWSYDLWGRGT LVTVSS (residues 1-120 of SEQ ID NO:6); and
said antibody comprises a light chain variable region (VL) of an M25FYIA antibody comprising the amino acid sequence QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYDVTNRPSG VSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTIASTLVVFGGGTKLTVL (residues 136-246 of SEQ ID NO:6).
5. The antibody of claim 1 , wherein said antibody is selected from the group consisting of an intact immunoglobulin, an Fv, a Fab, a (Fab′) 2 , a (Fab′) 3 , an IgGΔCH2, and a single-chain antibody.
6. An immunoconjugate comprising the antibody of claim 1 attached to an effector wherein said effector is selected from the group consisting of a second antibody, a detectable label, a cytotoxin or cytostatic agent, a liposome containing a drug, a radionuclide, a drug, a prodrug, an immune modulator, a viral particle, a cytokine, and a chelate.
7. The immunoconjugate of claim 6 , wherein said effector is a second antibody.
8. The immunoconjugate of claim 7 , wherein said second antibody is an antibody that binds to CD3.
9. The immunoconjugate of claim 6 , wherein:
said antibody comprises a heavy chain variable region (VH) of an M25FYIA antibody comprising the amino acid sequence QVQLQQSGGGLVKPGGSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISYDGSN KYYADSVKGRFTISRDNSKNTLYLQMDSLRAEDTAVYYCAKEGDSSRWSYDLWGRGT LVTVSS (residues 1-120 of SEQ ID NO:6); and
said antibody comprises a light chain variable region (VL) of an M25FYIA antibody comprising the amino acid sequence QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYDVTNRPSG VSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTIASTLVVFGGGTKLTVL (residues 136-246 of SEQ ID NO:6).
10. The immunoconjugate of claim 6 , wherein said antibody is an intact immunoglobulin.
11. A pharmaceutical formulation said formulation comprising:
a pharmaceutically acceptable carrier and the antibody of claim 1 .