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Complex of alpha-fetoprotein and inducers of apoptosis for the treatment of cancer

a technology of alpha-fetoprotein and apoptosis, which is applied in the field of cancer medicine and oncology, can solve the problems of limited afp source, lack of specificity of preparation, and complicated conjugation step of anticancer conjugates

Inactive Publication Date: 2007-05-17
PAK VLADIMIR +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0009] The present invention may provide one or more of the foregoing advantages or other advantages which will become apparent to persons skilled in the art after review of the present application.

Problems solved by technology

However, these preparations lack specificity in that they do not specifically target tumor cells.
However, the binding procedure of HAFP to these anticancer drugs requires a prior step of conjugation with HAFP.
This additional conjugation step not only complicates the preparation of such anticancer conjugates (i.e. HAFP-doxorubicin) but forces the covalent binding of HAFP and anticancer drug by chemical modification of HAFP.
Moreover, these prior art methods have all focused on invasive methods of administration (e.g. injection) using human AFP which is an expensive and a limited source of AFP.
This loss of anticancer drugs requires a higher dosage which leads not only to an increase in the costs of production but also increases the possibility of potential side effects to the treatment.
This step must occur before the conjugation step and contributes to the high cost of purified HAFP.
Since many tumor cells demonstrate multi-drug resistance (MDR), the use of only one anticancer drug in the prior art methods (i.e. HAFP-estrone-doxorubicin conjugate) is a limiting factor in the treatment of malignant neoplasms.
Finally, the prior art anticancer drugs are alkylating agents and antibiotics which target the DNA and therefore are not fully effective as it is known that 50% of cancers have damaged p53 protein (Bykov, V J et al., Nat. Med. 8(3):282-8, 2002).

Method used

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  • Complex of alpha-fetoprotein and inducers of apoptosis for the treatment of cancer
  • Complex of alpha-fetoprotein and inducers of apoptosis for the treatment of cancer
  • Complex of alpha-fetoprotein and inducers of apoptosis for the treatment of cancer

Examples

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Effect test

example 1

PAFP Isolation and Purification

[0041] PAFP is collected from the liver and blood of porcine embryos, the amniotic fluid, and the placenta. The time of collection of the fluids is crucial during the pregnancy since it affects the properties of PAFP influencing the parameters and success of the pre-binding step. If collected too early or too late, the glycosylation of PAFP is different and the subsequent binding properties of PAFP are changed. The best time to collect the raw material containing PAFP is between the 6th and 14th week of embryogenesis. The period of collection of the fluids from the embryo is important as the glycosylation of PAFP varies during embryogenesis and the yield of fluids diminishes significantly after the 14th week of gestation.

[0042] The blood and amniotic fluid is kept at 4-10° C. for 12 to 24 hours for natural sedimentation. The supernatant is collected and transferred to a different container. The supernatant is concentrated 3-5 times by ultrafiltratio...

example 2

PAFP is Bioequivalent to HAFP

[0044] It was not known if PAFP exhibits the same biological properties as HAFP. Therefore, we tested our preparation of PAFP with 2 immuno enzyme kits for quantitative determination of alpha-fetoprotein in human serum and amniotic fluid. The first one is a membrane EIA Alpha-fetoprotein test (cat. #410-1 produced by IND Diagnostic Inc., Vancouver, Canada) which uses a monoclonal antibody to HAFP. The results were negative confirming a difference of HAFP and PAFP in their chemical structure. The second kit that was used contains a polyclonal antibody to HAFP (T-8456-T-8456-AFP-EIA-BEST-Strip“, manufactured by Vector-BEST, Novosibirsk, Russia) which detected the presence of PAFP. It was not known if PAFP would provoke the same biological response as HAFP (i.e. apoptosis) as the amino-acid ratio for the porcine source is different from the human source. To determine if PAFP is bio-equivalent to the human AFP (HAFP) we: [0045] a. checked if PAFP would bin...

example 3a

In Vitro Binding of PAFP and the First Compound

[0047] The upper phase containing unbound PAFP and the first compound (at least one type of anticancer drug) are mixed for one minute and will incubate for an additional 10 minutes at 10-15° C. to allow for the binding of PAFP and the first compound to form a PAFP-first compound mixture. The incubation may occur for a longer time however we find that there is no significant benefit to increasing the time of incubation. The PAFP-first compound mixture then undergoes ultrafiltration using a 50 kDa membrane. We use the diafiltration process to remove small molecules and other non-desired elements (i.e. impurities) such as the salt which is used as a biological buffer during the collection of the raw material (embryo's fluids). We also use the diafiltration step to get rid of any unbound first compound.

[0048] The non-desired elements from the diafiltration are discarded as filtrate and the retentate, containing the PAFP-first compound mi...

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Abstract

The invention relates to a composition comprising exogenous alpha-fetoprotein, a first compound reversibly bound to exogenous alpha-fetoprotein in vitro, and an unbound second compound wherein the first and second compound are anticancer drugs or combinations of anticancer drugs and wherein the second compound reversibly binds to recycled exogenous alpha-fetoprotein in vivo. A process for the butanol extraction of alpha-fetoprotein obtained from porcine blood and amniotic fluid during early embryogenesis and a process for the in vitro binding of alpha-fetoprotein and a first compound are also described. The invention also relates to a method of using these compositions to prevent, treat or inhibit a malignant neoplasm expressing an alpha-fetoprotein receptor.

Description

FIELD OF INVENTION [0001] The present invention relates to the field of medicine, oncology in particular, and can be used for the treatment of cancer in humans and animals. BACKGROUND OF THE INVENTION [0002] During ontogeny in mammals and other vertebrates, some proteins are produced at various stages of embryonic fetal and neoplastic growth. These proteins are termed oncofetal antigens as they can be found in fetal and tumor-associated growth. They may appear, disappear or vanish to small amounts depending on the specific phase of development. Alpha-fetoprotein (AFP) is an example of one such oncofetal antigen and is a member of the albuminoid gene superfamily. The molecular weight of AFP can vary from 64,000 to 72,000 daltons depending on the animal and origin and the method used for its purification. AFP is a glycoprotein containing 3-5% carbohydrate which percentage also varies depending on the animal and origin. [0003] AFP appears to be present in two basic molecular forms: 1) ...

Claims

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Application Information

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IPC IPC(8): A61K38/40A61K31/57A61K31/445A61K33/36
CPCA61K31/445A61K31/57A61K33/36A61K35/48A61K35/50A61K38/1709A61K45/06A61K2300/00A61P35/00A61P35/04A61P43/00A61K38/00
Inventor PAK, VLADIMIRGAGNE, STEPHANE
Owner PAK VLADIMIR
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