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Competitive Comparison

The drugs, Crotoxin and VRCTC-310, possess several desirable properties as therapeutics:

1. Broad activity against a variety of tumour cell types.
2. They are potent - a little goes a long way.
3. They have good therapeutic windows. They induce tolerance permitting the use of higher than toxic doses to be employed.
4. They exhibit minimal adverse side effects and they are well tolerated by patients.
5. Their production is relatively simple and the drugs are stable.
6. They are easy to administer - simple subcutaneous or intra-muscular injection.
7. Early studies indicate a significant analgesic effect.

Crotoxin

Crotoxin (CT), a cytotoxic PLA₂-containing complex, is a bi-partite protein extracted from the venom of Crotalus durissus terrificus (a tropical snake). CT can be dissociated into two non-identical subunits, A & B. Subunit A has no enzymatic activity and is not toxic while subunit B contains the PLA₂ toxic enzyme. For its anticancer action CT requires enzymatic PLA₂ activity and also the dissociation of its two subunits:

For many years now, cancer researchers have been investigating the use of targeting agents, namely monoclonal antibodies, to carry a toxic substance, i.e. a toxin, to the tumour site. CT appears to have an inherent targeting mechanism. It has been suggested that it is in the targeting of PLA₂ enzymes to specific tissues or cells that unique toxicities are produced. Such target cells may possess receptor sites that are recognized by a specific site on the enzyme surface. This determines the binding of the PLA₂ to the cell membrane and the subsequent phospholipid hydrolysis that results in cell death.

CT also displays an interesting degree of activity and selectivity. In vitro, the anti-tumour activity of the CT complex is extremely rapid (and not dependent on the cell cycle). For example, CT produced 68% killing after 1 hr incubation with murine (mouse) erythroleukemia cells and after 12.5 hr the killing was 100%. With the human mammary tumour cell line Hs 578T, the exposure to CT killed 90% of the cells in 6 hr. However, exposure of normal human keratinocytes cultures to CT showed that 60% of healthy cells were still viable after four days incubation.

To examine the anti-tumour action of CT relative to other chemotherapeutic agents it was compared to preclinical in vivo results on Lewis lung carcinoma obtained by the National Cancer Institute for standard anticancer agents:

Cardiotoxin

The Company is also investigating a membrane-disruptive peptide called Cardiotoxin (CD). CD (6 kDa) is isolated with ease from the venom of Naja naja atra and other cobras. CD is a basic amphipathic peptide of relatively weak lethal toxicity when administered by the intra-muscular (i.m.) route (LD₅₀ (Lethal Dose) i.m. in mice 52 mg/kg; in rats 65 mg/kg). Due to its mechanism of action it is also known as a membrane disruptive peptide. CD has been shown to perturb cell membranes by insertion into the lipid phase. Although in vitro it has proved to selectively lyse transformed rather than normal cells and be highly cytotoxic to a variety of tumour cell types, however, in vivo it has not displayed significant anti-tumour activity. CD has been mostly studied because of its synergism with PLA₂s. In cell lysis, such synergism between CD and PLA₂s is thought to result from CD-mediated action that alters the membrane structure and facilitates phospholipid hydrolysis by the enzyme. The Company will continue to study this drug.

VRCTC-310

Studies have been conducted on a combination of CT and CD which have resulted in a new research product, VRCTC-310. The contribution of the CD component to VRCTC-310 is the result of particular pharmacologic interactions with CT and is related to potentiating CT PLA₂ activity, and thus cytotoxicity with the added benefit of reducing its non-tumour directed toxicity. As a result, this combination product has an enlarged "therapeutic window" (the difference between the therapeutic and the unwanted toxic doses).

The National Cancer Institute (USA) found that VRCTC-310/Crotoxin exhibited a unique pattern of activity against Central Nervous System (CNS) tumours, melanoma and, to some extent, the lung tumour cell lines. This pattern of activity was found to be unlike that for any known agent for which a mechanism of cell killing had been determined. Analysis of the NCI in vitro data shows that the addition of CD to CT in the VRCTC-310 product results in a potentiation of up to 60% (CNS). In general, the combination of these two agents results in a synergistic increase in in-vitro potency rather than a simple additive effect. The effects of VRCTC310 was examined in-vivo in mice models with implanted cancers and positive responses were observed using growth inhibition and life spans as endpoints. The Company will continue to conduct studies into this drug with a view to future clinical trials.

Intellectual Property - Ventech Inc. (Massachusetts, USA)

Ventech's research is based on peptides that selectively target specific cell membranes. Its drug development strategy is focused on novel cancer therapy and pain treatment products that would act therapeutically by recognizing differences on diseased cell membranes. The company applied for and received two (2) patents;

1. USPTO 5,164,196; "Crotoxin complex as cytotoxic agent", Inventors: GJH Plata, LA Costa, CM Vidal and JC Vidal, Assignee Ventech Research Inc., Issued in November 1992.
2. USPTO 5,232,911; "Mixture of a non-covalent heterodimer complex and a basic amphiphatic peptide as a cytotoxic agent", Inventor: JC Vidal, Assignee: Ventech Research Inc. Issued in August 1993.

Intellectual Property - Celtic Biotech Ltd.

In addition to having exclusively licenced VRI's technology, Celtic Biotech has two patent applications pending;

1. "Use of Crotoxin as an analgesic", for uses of Crotoxin as a substitute for morphine.
2. "Method of use of Crotoxin as an Anti-Retroviral agent" The application relates to a composition of matter involving a class of proteins like Crotoxin and a method of use of that composition for treatment of HIV-like diseases.

Other patent applications are in development and will be added when they have been filed.

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