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VITAMIN RECEPTOR BINDING DRUG
DELIVERY CONJUGATES
CROSS-REFERENCE TO RELATED
APPLICATIONS
This application claims priority under 35 U.S.C. § 119(e) to U.S. patent application Ser. No. 60/442,845, entitled "Vitamin-Receptor Binding Drug Delivery Conjugates," filed Jan. 27, 2003, U.S. patent application Ser. No. 60/492,119, entitled "Vitamin-Receptor Binding Drug Delivery Conjugates," filed Aug. 1,2003, andU.S. patent application Ser. No. 60/516,188, entitled "Vitamin-Receptor Binding Drug Delivery Conjugates," filed Oct. 31, 2003. The entirety of the disclosures of each of these applications are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to compositions and methods for use in targeted drug delivery. More particularly, the invention is directed to vitamin receptor binding drug delivery conjugates for use in treating disease states caused by pathogenic cell populations and to a method and pharmaceutical composition therefor.
BACKGROUND
The mammalian immune system provides a means for the recognition and elimination of tumor cells, other pathogenic cells, and invading foreign pathogens. While the immune system normally provides a strong line of defense, there are many instances where cancer cells, other pathogenic cells, or infectious agents evade a host immune response and proliferate or persist with concomitant host pathogenicity. Chemotherapeutic agents and radiation therapies have been developed to eliminate, for example, replicating neoplasms. However, many of the currently available chemotherapeutic agents and radiation therapy regimens have adverse side effects because they work not only to destroy pathogenic cells, but they also affect normal host cells, such as cells of the hematopoietic system. The adverse side effects of these anticancer drugs highlight the need for the development of new therapies selective for pathogenic cell populations and with reduced host toxicity.
Researchers have developed therapeutic protocols for destroying pathogenic cells by targeting cytotoxic compounds to such cells. Many of these protocols utilize toxins conjugated to antibodies that bind to antigens unique to or overexpressed by the pathogenic cells in an attempt to minimize delivery of the toxin to normal cells. Using this approach, certain inmnunotoxins have been developed consisting of antibodies directed to specific antigens on pathogenic cells, the antibodies being linked to toxins such as ricin, Pseudomonas exotoxin, Diptheria toxin, and tumor necrosis factor. These inmunotoxins target pathogenic cells, such as tumor cells, bearing the specific antigens recognized by the antibody (Olsnes, S.,Immunol. Today, 10, pp. 291-295,1989; Melby, E. L., Cancer Res., 53(8), pp. 1755-1760, 1993; Better, M. D., PCT Publication Number WO 91/07418, published May 30, 1991).
Another approach for targeting populations of pathogenic cells, such as cancer cells or foreign pathogens, in a host is to enhance the host immune response against the pathogenic cells to avoid the need for administration of compounds that may also exhibit independent host toxicity. One reported strategy for immunotherapy is to bind antibodies, for
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example, genetically engineered multimeric antibodies, to the surface of tumor cells to display the constant region of the antibodies on the cell surface and thereby induce tumor cell killing by various immune-system mediated processes (De 5 Vita, V. T, Biologic Therapy of Cancer, 2d ed. Philadelphia, Lippincott, 1995; Soulillou, J. P, U.S. Pat. No. 5,672,486). However, these approaches have been complicated by the difficulties in defining tumor-specific antigens.
l o SUMMARY OF THE INVENTION
In an attempt to develop effective therapies specific for pathogenic cells and with minimized toxicity for normal cells, vitamin receptor binding drug delivery conjugates have
15 been developed. The present invention is applicable to populations of pathogenic cells that cause a variety of pathologies in host animals. The pathogenic cells that can be treated with the drug delivery conjugates of the present invention include tumor cells, infectious agents such as bacteria and viruses,
20 bacteria- or virus-infected cells, and any other type of pathogenic cells that uniquely express, preferentially express, or overexpress vitamin receptors or receptors that bind vitamin analogs or derivatives.
In one embodiment there is provided a vitamin receptor
25 binding drug delivery conjugate. The drug delivery conjugate comprises a vitamin receptor binding moiety, a bivalent linker, and a drug. As used herein, "V" refers to a vitamin receptor binding moiety and includes vitamins, and vitamin receptor binding analogs or derivatives thereof, and the term
30 "vitamin or analog or derivative thereof refers to vitamins and analogs and derivatives thereof that are capable of binding vitamin receptors. As used herein, "D" refers to drugs and includes analogs or derivatives thereof. The vitamin, or the analog or the derivative thereof, is covalently bound to the
35 bivalent linker (L), and the drug, or the analog or the derivative thereof, is also covalently bound to the bivalent linker (L). The bivalent linker (L) can comprise multiple linkers. For example, the bivalent linker (L) can comprise one or more components selected from spacer linkers (ls), releasable link
40 ers (lr), and heteroatom linkers (1^), and combinations thereof, in any order.
Drug delivery conjugates that illustrate this embodiment include:
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V-L-D V-(U-D V-(U,-D V-(U,-(a-D 50 V-(lr)c-(U,-D
v-(Wk(U-D
v-ca-a^-D
V-(W),r(a-(W)e-D
...
v-CU-CWkCU-D
55 ...
...
...
...
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wherein a, b, c, d, and e are each independently 0, 1,2, 3, or 4, (ls), (lH), and (lr) are as defined herein, V is a vitamin, or analog or derivative thereof, and D is a drug, or analog or 65 derivative thereof, and where the bivalent L encompasses one or a variety of (1J, (1^), and (lr), in any order and in any combination. It is understood that the foregoing examples of
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