Targeting of biomolecules

Details Targeting of biomolecules Targeting of biomolecules

2000-10-12

2004-04-20

Witz, Jean C. (Department: 1651)

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

Extracorporeal or ex vivo removal of antibodies or immune...

C604S004010, C604S005010, C604S028000

Reexamination Certificate

active

06723318

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a methods of improving the tumor to non-tumor ratio of cytotoxic targeting agents in the treatment of disseminated carcinomas, in particular ovarian carcinomas, by reducing the concentration of the cytotoxic medical agent in the blood circulation after intraperitoneal administration of a cytotoxic agent and thereby facilitating a higher dosage and thereby a more effective treatment regime without exposing the vital organs to higher toxicity.
Among the various methods presented in this invention, means of extracorporeal removal of the circulating toxic agents is particularly attractive.
BACKGROUND OF THE INVENTION
Ovarian cancer is the sixth most common cancer among women, excluding non-melanoma skin cancers. The American Cancer Society estimates that about 23,100 new cases of ovarian cancer will be diagnosed in the United States during 2000. Ovarian cancer accounts for 4% of all cancers in women.
Ovarian cancer is also the fifth most common cause of cancer deaths among women, causing more deaths than any other cancer of the female reproductive system. It is estimated that there will be about 14,000 deaths from ovarian cancer in the United States during 2000. About 78% of ovarian cancer patients survive one year after diagnosis and over 50% survive longer than five years after diagnosis. If diagnosed, and treated while the cancer has not spread outside the ovary, the five-year survival rate is 95%. However, only 25% of all ovarian cancers are found at this early stage.
The 5-year survival rate refers to the percent of patients who survive at least 5 years after their cancer is diagnosed. Five-year relative survival rates exclude from the calculations patients dying of other diseases, and are considered to be a more accurate way to describe the prognosis for patients with a particular type and stage of cancer. Of course, 5-year survival rates are based on patients diagnosed and initially treated more than 5 years ago. Improvements in treatment often result in a more favorable outlook for recently diagnosed patients.
There are many types of tumors that can start growing in the ovaries. Some are benign (non-cancerous) and never spread beyond the ovary. These patients can be cured by surgically removing one ovary or the part of an ovary containing the tumor. Other types of ovarian tumors are malignant (cancerous) and may spread to other parts of the body.
In general, ovarian tumors are named according to the kind of cells the tumor started from and whether the tumor is benign or cancerous. There are three main types of ovarian tumors. Epithelial tumors start from the cells that cover the outer surface of the ovary. Cancerous epithelial tumors are called carcinomas. Germ cell tumors start from the cells that produce the eggs (ova). Stromal tumors start from connective tissue cells that hold the ovary together and produce the female hormones, oestrogen and progesterone.
Epithelial ovarian carcinomas (EOC) accounts for 85%-90% of ovarian cancers. The cells of EOC may have several forms that can be recognized under the microscope. In addition to their classification by cell type, EOCs are also given a grade and a stage. The grade is on a scale of 1, 2, or 3. Grade 1 EOC more closely resembles normal tissue and tends to have a better prognosis. Grade 3 EOC less closely resembles normal tissues and usually has a worse outlook. The tumor stage describes how far the tumor has spread from where it started in the ovary.
Effective therapeutic methods for the treatment of ovarian cancer have been subjected to intensive research. Most women suffering from ovarian carcinomas die of loco-regional recurrence and peritoneal dissemination; hence, regional therapy has been the main focus for some time. Experience with intraperitoneal therapy of this tumor using conventional chemotherapy agents (Howel S. et. al. Intraperitoneal cisplatinum-based chemotherapy for ovarian carcinoma,
Semin. Oncol
. 1991,18 (Suppl 3), 5-10); radioactive colloids (Rosenhein N. B. et. al. Radiocolloids in the treatment of ovarian cancer,
Obstet Gynecol Surv
1997, 34, 708-20); immunoadjuvants (Bast R. C. et. al. Intraperitoneal immunotherapy of human ovarian carcinoma with corynebacterium parvum.
Cancer Res
. 1983, 43, 1395-1401); cytokines (Navoli M. et. al. Intraperitoneal recombinant alpha-2-interferon alternating with cisplatin as salvage therapy for minimal residual-disease ovarian cancer: a phase II study.
J. Clin. Oncol
1990, 8(6), 1036-1041) have been reported.
Another area of investigation involves treatment with very high doses of anticancer drugs, and then “rescuing” the woman from the side effects with infusions of her own bone marrow stem cells or peripheral blood stems cells (immature blood cells that may be taken from the bone marrow or removed from the bloodstream by using a special filtering process). The bone marrow or peripheral blood stem cells are removed before a high dose of chemotherapy is administered and is returned to the woman (reinfused) after the high-dose treatment is complete. In that way, the side effect of suppressed blood cell production is overcome. This is an extremely high-risk, experimental procedure because, for the time, the woman is without her normal supply of blood cells and is very vulnerable to infection.
Targeting biomolecules such as tumor specific monoclonal antibodies are widely used in the treatment of haematological cancer diseases and more recently in the treatment of disseminated solid tumors (Breitz H. B. et. al. Radioimmunotherapy of Solid Tumours, in
Radioimmunotherapy of Cancer
, eds. P. G. Abrams & A. R. Fritzberg, Marcel Dekker, Inc., New York, 2000, p.265-306).
A number of tumor specific monoclonal antibodies and immunoconjugates, suitable for in vivo diagnosis and treatment of ovarian cancer, have been described in U.S. Pat. No. 4,958,009 (Anti-human ovarian cancer immunotoxins and methods of use thereof), in U.S. Pat. No.5,817,313 (Monoclonal antibodies and conjugates thereof useful for the treatment of cancer), in U.S. Pat. No. 5,804,187 (Modified antibodies with human milk fat globule specificity) and in U.S. Pat. No. 5,650,291 (Monoclonal antibodies against an antigen associated with ovarian cervical and other tumors).
Over the past decade a number of clinical studies using intraperitoneal (i.p.) radioimmunotherapy in ovarian cancer have been reported. Various types of monoclonal antibodies including HMFG-1, HMFG-2, AUA-1 and H 17E2 have been labelled with I-131, Y-90 and Re-186, and injected into the peritoneal cavity through peritoneal dialysis catheter under local anaesthesia in volumes ranging from 1-2 liter of normal saline and a specific activity of 4-8 mCi/mg antibody.
The effective dose for i.p. I-131 labelled antibodies is thought to be 150 mCi and the mean peak radioactivity in serum is at 44 hrs, corresponding to 26% of the total injected dose. Most of the radioactivity given (80%) is found as free iodine in the urine. However, when Y-90 labelled antibodies are used, the mean peak of radioactivity in serum is 23%, and only 8-11% of the injected dose is released in the urine after 72 hrs (Rosenblum M. G. et. al. Clinical pharmacology, metabolism and tissue distribution of Y-90-labelled monoclonal antibody B27.3 after intraperitoneal administration.
J. Natl. Cancer Inst
. 1991 (83) 1629).
Although, toxic exposure to the peritoneum and its close surrounding is usually well tolerated and is 4-70-fold more advantageous than the i.v. route for targeting of peritoneal tumor sites (Ward, B. G. et. al. Localization of radio iodine conjugated to the monoclonal antibody HMFG-2 in human ovarian carcinoma: assessment of intravenous and intraperitoneal routes of administration.
Cancer Res
. 1987 (47) 4719; Ward B. G. et. al. Radiolabelled monoclonal antibodies in oncology. III Radioimmunotherapy.
Nucl. Med. Commun
. 1991 (12) 333), a high percentage of the injected activity still localizes in normal tissues; the dose-limiting organ being the bone marrow. Myelosuppression arises 4-6 weeks after the initia

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