Combined methods and compositions for tumor vasculature targeting and tumor treatment
View Patent ↗The present invention relates generally to methods and compositions for targeting the vasculature of solid tumors using immunological- and growth factor-based reagents. In particular aspects, antibodies carrying diagnostic or therapeutic agents are targeted to the vasculature of solid tumor masses through recognition of tumor vasculature-associated antigens, such as, for example, through endoglin binding, or through the specific induction of endothelial cell surface antigens on vascular endothelial cells in solid tumors.
1. A method for treating an animal having a vascularized tumor, comprising:
administering to said animal an amount of a construct effective to treat said vascularized tumor; said construct comprising a selected therapeutic agent linked to a targeting agent that binds to a marker expressed, accessible to binding or localized on the cell surfaces of intratumoral blood vessels of the vascularized tumor; and
administering to said animal a chemotherapeutic agent or an antitumor drug.
2. The method of claim 1 , wherein said targeting agent is a monoclonal antibody or monoclonal antibody fragment.
3. The method of claim 2 , wherein said antibody recognizes ELAM-1, VCAM-1, ICAM-1, a ligand reactive with LAM-1 or endoglin.
4. The method of claim 2 , wherein said antibody binds to a growth factor localized on the cell surface of intratumoral blood vessels of a vascularized tumor, wherein said growth factor binds to an intratumoral vasculature cell surface receptor.
5. The method of claim 2 , wherein said antibody binds to a complex of a growth factor and a growth factor receptor present on the surface of intratumoral blood vessels of the vascularized tumor, but that does not bind to the individual growth factor or growth factor receptor.
6. The method of claim 1 , wherein said targeting agent is a growth factor.
7. The method of claim 1 , wherein said targeting agent is linked to an anticellular agent capable of killing or suppressing the growth or cell division of endothelial cells.
8. The method of claim 7 , wherein said anticellular agent is a chemotherapeutic agent, radioisotope or cytotoxin.
9. The method of claim 8 , wherein said anticellular agent is a steroid, a cytokine, an antimetabolite, an anthracycline, a vinca alkaloid, an antibiotic, an alkylating agent, an epipodophyllotoxin, a plant-, fungus- or bacteria-derived toxin, an A chain toxin, bacterial endotoxin, the lipid A moiety of bacterial endotoxin, a ribosome inactivating protein, gelonin, α-sarcin, aspergillin, restrictocin, a ribonuclease, diphtheria toxin, Pseudomonas exotoxin, ricin A chain or deglycosylated ricin A chain.
10. The method of claim 1 , wherein a chemotherapeutic agent is administered to said animal.
11. The method of claim 1 , wherein an antitumor drug is administered to said animal.
12. The method of claim 10 , wherein said chemotherapeutic agent is an antimetabolite, an anthracycline, a vinca alkaloid or an antitumor alkylating agent.
13. The method of claim 10 , wherein said chemotherapeutic agent is cytosine arabinoside, fluorouracil, methotrexate, aminopterin, mitomycin C, demecolcine, etoposide, mithramycin, chlorambucil, melphalan, doxorubicin, daunomycin, vinblastine, neocarzinostatin, macromycin, trenimon or α-amanitin.
14. The method of claim 1 , wherein said animal is a human patient.