Cancer therapies that utilize site-specific drug

systems provide the focus for a new UK bio-

pharmaceutical company. Launched in June

1998, Enzacta will work in the discovery and

development of major cancer therapies using

site-specific effects, drawing upon the experi-

ence and expertise of its senior scientific team

and the integrated technology base, including

targeting agents, enzymes, clearance agents

and drugs, upon which it is founded. Enzacta

already has therapies through research and into

development, and its lead product is due to

enter clinical trials in late 1998.

The company was launched by Kenneth

Bagshawe and Jon Dickens. Bagshawe is a

former chairman of the Cancer Research

Campaign’s (CRC) executive committee who later

formed Aepact, a company that was to focus on

the production of second- and third-generation

therapies based on his discovery of antibody-di-

rected enzyme prodrug therapy (ADEPT). Jon

Dickens was a founder of British Biotech and for-

mer executive director at Chiroscience. In the

summer of 1996, a group of entrepreneurs

formed ProDrug Pharma as the commercial and

financial vehicle for Aepact and, after raising £2

million in the interim, this year the two compa-

nies were brought together to form Enzacta. The

company’s main facility is to be based at Porton

Down Science Park (Salisbury, UK), and this will

house the company’s protein chemistry, molecu-

lar biology, pharmacology and medicinal chem-

istry groups. However, due in part to Bagshawe’s

long-term association with Charing Cross

Hospital (London, UK), the company will retain a

foothold within the hospital in order to maintain

what the company sees as vital close contact

with its CRC clinical trials organization and to

have access to the hospital’s preclinical facility.

Site-specific drug effectsAccording to Enzacta, conventional antibody

targeting is limited by the fact that the target

antigen is not expressed by all tumour cells and

by drug carrying capacity. The company claims

that, through the employment of enzymes, its

therapies will overcome these problems because

a single enzyme can activate or deactivate many

thousands of drug molecules. Use of the enzyme

technology will enable generation of high drug

concentration in the vicinity of the target cell

and allows diffusion of drug into adjacent cells.

The company’s integrated technology base is

key to the company’s attempts to develop

major cancer therapies. This technology base

supports two different modes of therapy, and in

both cases enzyme is delivered specifically to

tumour sites. The tumour-located enzyme is

then used in two different ways.

• To generate a cytotoxic drug from a prodrug

– macromolecular directed enzyme prodrug

therapy (MDEPT)

• To destroy an agent that protects cells from

a cytotoxic agent – anti-metabolite with in-

activation of rescue agent at cancer sites

(AMIRACS)

The company claims that each mode can de-

velop into multiple individual therapies. The

MDEPT system features three stages, beginning

with enzyme polymer conjugate that localizes

at cancer sites and residual enzyme conjugate

that is found in normal tissue. Stage two in-

volves the intravenous administration of a

clearing agent 24 h after the enzyme conjugate

to facilitate the removal of the enzyme from

the normal tissue into the blood for clearance,

with the enzyme remaining in the tumours. In

the third stage, the prodrug is converted to a

drug by the enzyme conjugate and diffuses into

the cancer cells (Fig. 1). Figure 2 shows the

biodistribution of CPG2 activity in xenografted

nude mice after mice were given 25 units of the

enzyme (CPG2) MDEPT system, followed by the

clearance antibody. The data shows clearly that

the MDEPT system has localized enzyme suc-

cessfully in the tumour. According to Enzacta,

MDEPT-based therapies have the potential to

become a component in many cancer therapy

regimens, including applications in the treat-

ment of most solid tumours. Advantages in-

clude an increased tumour drug dose and less

toxicity relative to conventional chemotherapy,

and the company also claims that the therapies

are less immunogenic, and are easier and

cheaper to make, than antibody conjugates.

In the long-term, the company believes that

the versatility of MDEPT will result in major

breakthroughs in the treatment of colorectal,

breast, lung, prostate and stomach cancers. On

a commercial level, the technology platform will

also present the company with opportunities

for significant collaborations with other major

pharmaceutical companies in the development

of new therapies.

The company’s AMIRACS mode of therapy

also features three stages, and it has been

tested clinically in two patients with no re-

ported adverse effects: one patient showed

stabilization of the disease. Stage one is

marked by enzyme conjugate localized at can-

cer sites, but with the persistence of residual

enzyme conjugate in normal tissue. In stage

two, a clearance agent is administered after

24 h to remove the enzyme conjugate from the

normal tissue. In the third and final stage, at

48 h an antimetabolite drug is administered for

update news PSTT Vol. 1, No. 5 August 1998

184

New venture for targeted cancer therapyAdrian Smith, Pharmaceutical Science & Technology Today, tel: 144 1223 315961, fax: 144 1223 464430, e-mail: pstt@elsevier.co.uk

Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1461-5347/98/$19.00. PII: S1461-5347(98)00056-X

five days with a rescue agent, which is de-

stroyed at the cancer site by the enzyme conju-

gate. Thus the anti-metabolite drug can kill the

cancer cells without intervention of the rescue

agent. Components of the AMIRACS prototype

system are listed in Box 1, and advantages

include:

• cytotoxic drug and rescue agent are already

used in combination for Pneumocystis infections;

• drug components are available off the shelf;

• antibody–enzyme conjugate and clearing

antibody have already been tested in a clini-

cal environment, with no adverse effects;

• all materials necessary for immediate clini-

cal trial are available.

Enzacta holds the patents for both MDEPT

and AMIRACS. However, the company’s intellec-

tual property also includes patents for tech-

nologies such as effective nitroreductase action

in cancer therapy (ENACT). ENACT employs an

endogenous human enzyme that is overex-

pressed in some tumours and which is inactive

with the co-factors and the co-substrates used

by other similar human enzymes. In the pres-

ence of co-administered (patented) co-sub-

strates, the enzyme is capable of activating the

prodrug CB1954 (a proven anti-tumour agent

in rats) to a cytotoxic species that is at least

10,000 times more toxic. Other therapies in re-

search include intra-vascular inactivation of ac-

tive drug (IVIAD), internalizing antibody di-

rected enzyme prodrug therapy (IADEPT) and

small molecule enzyme prodrug (SMEIA). In the

case of both IVIAD and IADEPT, Enzacta owns

their respective patents and the patent for

SMEIA is licensed to Enzacta by the Post Natal

Chorioepithelial Trust.

The futureEnzacta’s long-term strategy centres around the

company’s integrated technology base. Also, in

addition to this integrated technology base, the

company also has six key patents filed to sup-

port its technology, experience of scale-up and

good manufacturing practice production of

protein conjugates, established in vivo and invitro methodology for the preclinical evaluation

and development of its therapies, and extensive

clinical experience.

The development of this base by the com-

pany’s senior scientific team will continue to

broaden the company’s options, and this may

involve the use of this base on currently mar-

keted drugs, on other companies drugs in devel-

opment and the further development of in-

house therapies. This strategy will ensure early

returns on investment, set in place the potential

for major collaborations and will create an op-

portunity in the long-term for the production of

therapies with blockbuster potential. The team

at Enzacta hope that this strategy will lead to

the development of innovative technologies that

will produce maximum therapeutic benefit to

cancer patients.

PSTT Vol. 1, No. 5 August 1998 update news

185

Box 1. Components of theAMIRACS prototype system

• Prototype system is based on theuse of the dihydrofolic reductoseantagonist trimetrexate

• Effects of trimetrexate can berescued by the administration ofleucovorin

• Leucovorin can be broken down bythe enzyme carboxypeptidase G2

(CPG2)• CPG2 can be targeted to carcino

embryonic antigen-expressingtumour cells by the antibody A5B7

Figure 1. Macromolecular directed enzyme prodrug therapy (MDEPT) activation of the prodrug attumour sites (stage 3). The prodrug is converted to a drug by the enzyme conjugate and this drugthen diffuses into the cancer cells.

Prodrug

Prodrug

Cancer cells

Enzyme

Drug

One enzyme converts hundreds of prodrugs drugs per min

Drug diffusesinto cells

Figure 2. The biodistribution of CPG2

activity in xenografted nude mice. The micewere given 25 units of the enzyme (CPG2)macromolecular directed enzyme prodrugtherapy (MDEPT) system, followed by aclearance antibody. The results show thatthe MDEPT system has successfullylocalized enzyme in the tumour.

Plasm

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1

1.5

2

Liver

Kidney

Tissues

CP

G2

activ

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Lung

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Tumou

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