Genetic Drug Carrier      

KK Biomed Corporation

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Genetic Drug Carriers

Introduction 

KK Biomed is an early stage pharmaceutical company with advanced drug carrier technologies for the treatment of cancer and other diseases. KK Biomed is a private corporation started in Utah, January 2000.  Our mission is to be a leading provider of carriers for genetic drugs and other drugs in the projected $8 billion drug carrier market.

There is a critical need for genetic drug carriers in the treatment of cancer and other diseases.  KK Biomed has developed a patented drug carrier to fill this need. 

KK Biomed Technology.

KK Biomed’s carriers are proprietary or patented micelle particles based on FDA approved substances such as cyclodextrin (CD) or polyethylene glycol (PEG).  CD and PEG have little or no toxicity or immunogenicity.  Micelles are microscopic particles well known for carrying small drugs and genetic drugs.  However, many micelles being developed are based on polymers that are not FDA approved.

Our lead product is a rationally designed, micelle carrier for administering genetic drugs intravenously.  We have initially targeted cancer chemotherapy because injection is a common route of administration.  Cancer is now the leading cause of death in the US and there is a demonstrated need for a genetic drug carrier.  Also, there are generally more accelerated or "Fast Track" FDA programs for cancer drugs.  Finally, cancer chemotherapy is a 13 to 26 billion dollar market worldwide.  Our carrier is also designed for eventual use in oral and pulmonary drug delivery.

Genetic drugs are small lengths of synthetic, "antisense" DNA or “small interfering” RNA (siRNA), that interfere with the protein metabolism of cancer cells or disease organisms.  Based on clinical trials and other data, KK Biomed believes that genetic drugs need a carrier for at least three critical reasons. 

First, genetic drugs in their "natural" form are unmodified nucleic acids that are easily broken down in the bloodstream without a protective carrier.  Therefore, most companies chemically modify genetic drugs to resist metabolism by enzymes and white blood cells.  Chemical modification adds to their expense, reduces solubility and, more critically, increases their toxicity.

Second, genetic drugs bind to blood proteins without a protective carrier.  This binding lowers drug availability and requires higher doses of drug to compensate.  Also, this is a random binding that is affected by the patient’s circulatory condition.  This can increase variation in dosage for different patients and even with the same patient at different times. 

Third, genetic drugs are so small that unbound drug can be cleared through the kidneys.  This removes them from circulation and again requires higher doses of drug to compensate.  The higher dosages contribute to higher toxicity and other side effects.

Advantages Over The Competition.

The use of micelle and liposome particles as genetic drug carriers is well known in the industry.  First, the carrier shields the genetic drug from excessive breakdown.  Second, using biocompatible chemistry with the carrier reduces the risk of binding to blood proteins.  Third, the drug loaded carrier is designed to be too large to be filtered through the kidneys. 

However, the composition of the micelle is critically important to having a carrier approved for human use.  Currently there is no FDA approved genetic drug carrier.

Some companies are developing micelle carriers based on conventional technology borrowed from tissue culture methods.  They use opposite charge attraction to form a complex between a high positively charged polymer and the negatively charged genetic drug.  These complexes are unstable in the bloodstream.

High charge is also commonly used to ensure release of the genetic drug into the cell.  Otherwise, the drug cannot work effectively.  This high charge approach introduces toxicity and instability, which requires "work around" solutions for FDA approval.  

KK Biomed uses a forward-looking, rational design where potential pitfalls such as high charge are minimized or eliminated.  First, KK Biomed’s approach is to start with FDA approved materials.  Many polymer materials currently being used are not FDA approved. 

KK Biomed has discovered an innovative coupling system that employs an FDA approved material specific for genetic drugs.  This provides the option of completely eliminating charge dependent complexes with certain genetic drugs. 

Using our coupling method, the same carrier system can be used with several different genetic drugs.  The problems and cost of re-engineering genetic drugs for coupling to polymers is eliminated. A patent is pending on this discovery.

Second, our carrier is not dependent upon charged complexes for release into the cell.  Once inside the cancer cell, the proprietary carrier releases the drug so that it can take effect.  KK Biomed has discovered that another FDA approved material in combination with our carrier, facilitates release into the cell.  There is a second patent pending for this discovery which may also be exploited in developing other drug formulations. 

Third, KK Biomed's carrier is a non-viral system that eliminates the allergic reactions and other problems seen with viral materials.  In spite of their risks, some companies are still pursuing viral carriers. 

Fourth, KK Biomed has recently been awarded a patent for using stabilized micelles as drug carriers.  Conventional micelle carriers need stabilizing because of uncontrolled loss of the drug by disruption or diffusion in the bloodstream.  Our technology meets that need through cross-linking the micelle to entrap the drug until it is delivered into the tumor. 

The micelle-forming components are designed to permit cross-linking after the micelle has been formed with a drug inside.  The cross-links contain “biocleavable” linkages meaning that the cross links are cleaved in the biological environment of a tumor cell. 

Also, to increase efficacy, the micelle carriers can be targeted by coupling antibodies or other targeting molecules to the surface.  Stabilized micelles also provide practical advantages needed for shipping and storage of the drug product. 

Finally, this technology opens the door to development of carriers for the oral and pulmonary delivery of both small drugs and genetic drugs.  With suitable selection of biocleavable linkages, drugs can be targeted for release in the stomach, lower digestive tract or lungs. In summary:

  KK Biomed Advantages                               Rationale                   .

Ø     FDA Starting Materials                                  Try to avoid obvious problems

Ø     Charge Independent Formula                        FDA material for coupling

Ø     Charge Independent Delivery                        FDA material to release the drug

Ø     Patented Micelle Cross Linking                     Bloodstream and shipping stability

Ø     Possible Oral, Lung Delivery                         Anticipate other delivery routes

Patent Protection.

KK Biomed has three patents on carrier technology and two pending applications.  U.S. Patent No. 6,048,736 was issued April 11, 2000, for the cyclodextrin drug carrier technology.  The patent consists of 19 claims.  This technology has the potential for penetrating several major therapeutic markets with patent protected products.  Some examples are genetic drug carriers to treat various cancers, arthritis, MS and infectious diseases such as AIDS. 

KK Biomed's second U.S. Patent No. 6,835,718 was issued December 28, 2004, for stabilized micelle compositions as drug carriers.  This patent has 10 claims and covers several synthesis methods for preparing the drug-carrying micelles. 

A European patent No. 1183 538 was granted April 14, 2004 that covers CD polymers as drug carriers.  Also, two more continuation-in-part (CIP) U.S. patent applications have been filed for other carrier compositions and drug formulations.

Background on Genetic Drugs

The side effects of conventional cancer chemotherapy are well known.  The side effects are caused by drugs that, while they kill cancers cells, they also damage normal cells in the body.

Genetic drugs are able to attack very specific metabolic functions in a cancer cell by "silencing" production of the proteins involved.  Since cancer cells are abnormal, they tend to have certain metabolic functions that are unusual and/or highly accelerated.  Genetic drugs can target specific cancer-linked proteins that are not critical in normal cells.

There are several types of genetic drugs being developed.  The most clinically advanced genetic drugs so far are made from short pieces of DNA called "antisense" ODNs (short for oligodeoxynucleotides) or “small interfering” RNA (siRNA). 

The Chemical Advantage of Genetic Drugs.

As a point of reference, it is accepted that therapeutic antibodies are highly valued by investors “because antibodies can be developed and put into clinical trials far faster than small molecule drugs – and with lower risk of failure, since proteins so similar to the body’s own are less likely to have toxic side effects than brand new chemical entities.” (Windhover Information Inc. 2001).

KK Biomed believes that genetic drugs fit into this same category with the same or more advantages compared to antibodies.  That is, genetic drugs are, in their simplest form, chemically identical to natural nucleic acids found in the body.  They are composed of natural building blocks arranged in specific sequences to target a known protein.  However, in this form they are also readily metabolized without protection. 

Therefore, they are usually chemically modified to resist metabolic destruction and this is where some toxicity is introduced.  KK Biomed believes that by using a protective carrier, the need for such modification can be drastically minimized or eliminated.

However, analogous to antibodies, even chemically modified genetic drugs have a consistent and predictable chemistry that is unaffected by what sequence is used to target a particular disease.  This a major advantage over small drugs that can vary tremendously since they are usually "new chemical entities" totally foreign to the body.

Antisense ODNs and especially siRNA are now being used routinely in the laboratory against many cancers in tissue culture, showing the "proof of principle".  One has been FDA approved against a virus disease and others such as Genasense™ are in clinical trials.

Genetic Drugs and Cancer.

It was discovered that many cancers become resistant to drug therapies by generating large amounts of a protein called bcl2.  An effective antisense ODN against bcl2, called Genasense™, is now being tested in human trials.

Multiple preclinical studies have shown that Genasense™ synergizes with most types of anticancer treatment, including chemotherapy, radiation, monoclonal antibodies and immunotherapy.  Based on preclinical data, Genta Inc. has conducted, or is currently conducting, preliminary clinical trials using Genasense™ in combination with:

Taxol® (Paclitaxel; Bristol Myers Squibb)

Camptosar® (Irinotecan; Pfizer, Inc.)

Gleevec® (Imatiinib Mesylate; Novartis)

Rituxan® (Rituximab; Genentech/IDEC)

Fludara® (Fludarabine; Berlex Laboratories, Inc)

Cytoxan® (Cyclophosphamide; Bristol Myers Squibb, Inc.)

Taxotere® (Docetaxel; Aventis Pharmaceuticals, Inc.)

Mylotarg® (Gemtuzumab ozogamicin; Wyeth-Ayerst, Inc.)

Every cell must make proteins, which control specific metabolic functions in the cell.  Proteins are made of chains of amino acids copied from a larger strand of nucleic acid called "messenger RNA" (mRNA).  The mRNA is a coded strand of nucleic acids called the "sense" strand that generates the correct protein.  Many mRNA codes have been deciphered for specific proteins. 

Genetic drugs are a new class of drugs based on these mRNA genetic codes.  Genetic drugs can target specific cancer-linked proteins by destroying the mRNA that makes the protein. 

Like two halves of a zipper, the sense strand of mRNA can be matched and bound by a synthetic antisense strand with the correct matching code.  A synthetic piece of antisense ODN or siRNA that binds to the mRNA, can block or destroy the mRNA that codes for a specific protein, which stops its function.  When a vital protein is targeted, the cancer cell can be killed. 

Many drug companies now recognize that a carrier system is needed that protects genetic drugs from degradation, nonspecific binding and early clearance in the bloodstream.  In conventional carriers, the negatively charged genetic drug is mixed with a positively charged carrier.  They bind together to form a complex that is unstable, especially in the bloodstream.

Therefore, conventional carriers require excess positive charge to increase stability.  Also, when a carrier enters a cell it usually enters a compartment called the endosome, where it can be trapped and destroyed.  So, it is critical to release the drug from the endosome into the cell.

Many conventional carriers require high charged polymers or lipids to release the drug.  Unfortunately, the high charge is toxic, and genetic anomalies have been reported, which may cause unexpected side effects.

KK Biomed has demonstrated that its carrier will deliver a coupled form of Genasense™ into cultured breast cancer cells. 

 Genetic Drug (Antisense) + Carrier Against Human Breast Cancer Cells

CD Carrier Animal Data Showing No Toxicity

Our plan is to position the company for a partnership or merger with a larger drug company by demonstrating the exclusive and competitive advantages of our rationally designed carriers.

E-mail for Information, Sales and Customer Support:  info@kkbiomed.com