Tumor homing molecules, conjugates derived therefrom, and methods of using same

Abstract

The present invention provides tumor homing molecules, which selectively home to a tumor. The invention also provides methods of using a tumor homing molecule to target an agent such as a drug to a selected tumor or to identify the target molecule expressed by the tumor. The invention also provides methods of targeting a tumor containing angiogenic vasculature by contacting the tumor with a molecule that specifically binds an alphav-containing integrin. The invention further provides molecules that can selectively home to angiogenic vasculature. In addition, the invention provides a target molecule, which is specifically bound by a tumor homing molecule and is expressed by angiogenic vasculature. The invention also provides antibodies that bind to the target molecule and peptidomimetics that competitively inhibit binding of a ligand to the target molecule.

Description

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 60 / ______, which was converted from U.S. Ser. No. 08 / 710,067, filed Sep. 10, 1996, the entire contents of which is incorporated herein by reference.FIELD OF THE INVENTION[0003] The present invention relates generally to the fields of cancer biology and drug delivery and, more specifically, to peptides that selectively home to a tumor, particularly a malignant tumor, to compositions comprising an agent such as a therapeutic agent conjugated to such tumor homing molecules, and to methods of using such molecules to target an agent to a tumor.BACKGROUND INFORMATION[0004] Continuous developments over the past quarter century have resulted in substantial improvements in the ability of a physician to diagnose a cancer in a patient. For example, antibody based assays such as that for prostate specific antigen now allow early diagnosis of cancers such as prostate cancer. More recently, methods of genet...

AI Technical Summary

Benefits of technology

[0012] The invention also relates to methods of targeting a moiety such as a drug to a tumor by contacting the tumor homing molecule / moiety conjugate with the tumor. Thus, the invention provides methods of diagnosing or treating a cancer in a subject by administering a composition comprising a tumor homing molecule conjugated to a cancer therapeutic agent to the subject. For example, administration of a composition comprising a doxorubicin / CDCRGDCFC (SEQ ID NO: 1) conjugate to a mouse bearing a transplanted breast carcinoma substantially reduced the growth of the breast cancer and the number of metastases and resulted in substantially greater survival as compared to tumor bearing mice treated with doxorubicin, alone, or with doxorubicin conjugated to an unrelated peptide.

Problems solved by technology

Unfortunately, methods for treating cancer have not kept pace with those for diagnosing the disease.

Thus, while the death rate from various cancers has decreased due to the ability of a physician to detect the disease at an earlier stage, the ability to treat patients presenting with more advanced disease has advanced only minimally.

A major hurdle to advances in treating cancer is the relative lack of agents that can selectively target the cancer, while sparing normal tissue.

For example, radiation therapy and surgery, which generally are localized treatments, can cause substantial damage to normal tissue in the treatment field, resulting in scarring and, in severe cases, loss of function of the normal tissue.

Chemotherapy, in comparison, which generally is administered systemically, can cause substantial damage to organs such as bone marrow, mucosae, skin and the small intestine, which undergo rapid cell turnover and continuous cell division.

As a result, undesirable side effects such as nausea, loss of hair and drop in blood cell count occur as a result of systemically treating a cancer patient with chemotherapeutic agents.

Such undesirable side effects often limit the amount of a treatment that can be administered.

Thus, cancer remains a leading cause of patient morbidity and death.

However, the use of molecules that can bind specifically to tumor vasculature and target a chemotherapeutic agent to the tumor has not been demonstrated.

While linking a drug to a molecule that homes to a tumor can provide significant advantages for treatment over the use of a drug, alone, use of this method is severely limited by the scarcity of useful cell surface markers expressed in a tumor.

Thus, where a tumor is present, for example, in the liver, nonspecific binding of molecules due to uptake by the RES can make identifying a tumor homing molecule more difficult.

However, such in vitro studies provide no insight as to whether a peptide that can specifically bind to a selected receptor in vitro also will bind the receptor in vivo or whether the binding peptide or the receptor are unique to a specific organ in the body.

However, such in vitro methods are limited in that they require prior knowledge of the target molecule and yield little if any information regarding in vivo utility.

Thus, in vitro panning methods using cells in culture also are limited in that there is no guarantee a molecule that is identified due to its binding to a cell in culture will have the same binding ability in vivo.

Furthermore, it is not possible using in vitro panning to distinguish molecules that home only to the tumor cells used in the screening, but not to other cell types.

Furthermore, in obtaining tumor homing molecules by in vivo panning, any molecules that may be particularly susceptible to degradation in the circulation in vivo due, for example, to a metabolic activity, are not recovered.

However, some cancers show patterns of metastasis that are not explained by circulatory routing.

Such an analysis is not possible using endothelial cells in culture because the cultured cells tend to lose their tissue-specific differences (Pauli and Lee, Lab. Invest. 58:379-387 (1988)).

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