Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
1999-03-11
2004-10-19
Helms, Larry R. (Department: 1642)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S154100, C424S194100, C424S195110, C424S198100
Reexamination Certificate
active
06805865
ABSTRACT:
TECHNICAL FIELD
The present invention relates to methods and compositions for preventing or reducing cancers in humans or animals. More particularly, the present invention relates to immunogenic compositions comprising growth factors, active fragments thereof, antibodies specific for growth factors, and methods of use thereof.
BACKGROUND OF THE INVENTION
While many cancers are treatable by chemotherapeutic agents, a significant number of cancers are intrinsically drug resistant and others acquire resistance during or following chemotherapy. Cancers frequently are resistant to more than one type of drug. This phenomenon is called multidrug resistance or MDR. Consequently, there is a great need for compositions and methods that can be used in addition to, or as alternatives to, chemotherapy for the treatment of cancer.
A major clinical problem of cancer is metastasis. By the time that the primary tumor is identified and localized, seed cells often have escaped and migrated or metastasized to other organs in the body where they establish secondary tumors. Surgical procedures are rarely sufficient to cure a cancer because even after the primary tumor is removed multiple secondary tumors survive and proliferate. Consequently, there exists an immediate and pressing need for techniques of eradicating secondary tumors that already exist.
Cancer cells that escape the primary tumor are usually carried in the venous and lymphatic circulation until they lodge in a downstream capillary bed or lymph node. However, only 1 in 10,000 of the cancer cells that escape the primary tumor survive to establish a secondary tumor. Successful cancer cells are those that find a favorable environment for survival and growth. The favorable environment include hormones and growth-promoting factors. Stimulating factors include local growth factors, hormones produced by the host, and autostimulating growth factors produced by the tumor cells themselves. Consequently, there is an immediate and pressing need for techniques capable of preventing or inhibiting metastasis of cancer and the formation of secondary tumors.
Additionally, many other hyperproliferative disorders exist. Hyperproliferative disorders are caused by non-cancerous (i.e. non-neoplastic) cells that overproduce in response to a particular growth factor. Examples of such hyperproliferative disorders include diabetic retinopathy, psoriasis, endometriosis, macular degenerative disorders and benign growth disorders such as prostate enlargement and lipomas.
It is known that many new cancers are initiated, and existing cancers and hyperproliferative disorders stimulated, by growth factors that affect either the cancer cell itself, or normal tissue around the cancer that facilitate survival of the cancer cell (i.e., angiogenesis factors). There is a direct correlation between the circulating level of certain growth factors and cancer proliferation. A potential method of treatment would be to regulate the level of circulating growth factors in a patient to prevent cancer initiation or recurrence, and to reduce or eliminate existing cancers. What is needed, therefore, are compositions that remove the target growth factors from circulation or inhibit the growth-promoting activity of growth factors.
Cellular proliferation is a normal ongoing process in all living organisms and is one that involves numerous factors and signals that are delicately balanced to maintain regular cellular cycles. The general process of cell division is one that consists of two sequential processes: nuclear division (mitosis), and cytoplasmic division (cytokinesis). Because organisms are continually growing and replacing cells, cellular proliferation is a central process that is vital to the normal functioning of almost all biological processes. Whether or not mammalian cells will grow and divide is determined by a variety of feedback control mechanisms, which include the availability of space in which a cell can grow, and the secretion of specific stimulatory and inhibitory factors in the immediate environment.
When normal cellular proliferation is disturbed or somehow disrupted, the results can affect an array of biological functions. Disruption of proliferation could be due to a myriad of factors such as the absence or overabundance of various signaling chemicals, growth factors or presence of altered environments. Some disorders characterized by abnormal cellular proliferation include cancer, abnormal development of embryos, improper formation of the corpus luteum, difficulty in wound healing as well as malfunctioning of inflammatory and immune responses.
Cancer is characterized by abnormal cellular proliferation. Cancer cells exhibit a number of properties that make them dangerous to the host, often including an ability to invade other tissues and to induce capillary ingrowth, which assures that the proliferating cancer cells have an adequate supply of blood. One of the defining features of cancer cells is that they respond abnormally to control mechanisms that regulate the division of normal cells and continue to divide in a relatively uncontrolled fashion until they kill the host.
Angiogenesis and angiogenesis related diseases are closely affected by cellular proliferation and therefore cytokines and growth factors. As used herein, the term “angiogenesis” means the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans or animals undergo angiogenesis only in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta. The term “endothelium” is defined herein as a thin layer of flat cells that lines serous cavities, lymph vessels, and blood vessels. These cells are defined herein as “endothelial cells”. The term “endothelial inhibiting activity” means the capability of a molecule to inhibit angiogenesis in general. The inhibition of endothelial cell proliferation also results in an inhibition of angiogenesis.
Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a “sprout” off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel.
Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, tumor metastasis and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions. The diverse pathological disease states in which unregulated angiogenesis is present have been grouped together as angiogenic-dependent, angiogenic-associated, or angiogenic-related diseases. These diseases are a result of abnormal or undesirable cell proliferation, particularly endothelial cell proliferation.
The hypothesis that tumor growth is angiogenesis-dependent was first proposed in 1971 by Judah Folkman (N. Engl. Jour. Med. 285:1182 1186, 1971). In its simplest terms the hypothesis proposes that expansion of tumor volume beyond a certain phase requires the induction of new capillary blood vessels. For example, pulmonary micrometastases in the early prevascular phase in mice would be undetectable except by high power microscopy on histological sections. Further indirect evidence supporting the concept that tumor growth is angiogenesis dependent is found in U.S. Pat. Nos. 5,639,725, 5,629,327, 5,792,845, 5,733,876, and 5,854,205, all of which are incorporated herein by reference.
One example of a disease mediated by angiogenesis is ocular neovascular disease
Holaday John W.
Madsen John
Plum Stacy M.
Ruiz Antonio
EntreMed, Inc.
Helms Larry R.
Kilpatrick & Stockton LLP
Yaen Christopher
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