Rick,
Here's a (long) cut 'n paste from Aquila's S-3:
The Company creates and commercializes products which modulate the immune
system to control, prevent or treat infectious diseases and cancers.
Aquila's technology and product development programs are based on
enhancement of the immune system using the Stimulon(TM) family of adjuvants.
Advances in biotechnology and immunology have enabled scientists to
develop a new generation of products which contain disease specific agents
and components which specifically modulate the immune system so that an
effective immune response is achieved. Traditional vaccines can prevent
infection through antibody based immune responses. While antibodies alone
can be effective in preventing or eliminating pathogen infection in
certain diseases, scientists now recognize that the cell mediated
response, where cytotoxic T lymphocytes ("CTL") are activated, is probably
necessary to eliminate intracellular pathogens. By stimulating a CTL
response it may be possible to develop therapeutic products to treat
diseases involving herpes, hepatitis and HIV infections or cancers.
The Stimulon(TM) family of adjuvants have been shown to enhance the quality
and the quantity of the immune response to a variety of antigens, both in
pre-clinical studies and in a number of human clinical trials. Aquila
believes that the Stimulon(TM) adjuvants will allow scientists to design
products which can activate specific T cell responses and result in a new
highly effective class of vaccines for both therapeutic and prophylactic
applications. The market potential of such products is high since this
new understanding of the immune system will allow expansion of the market
to address new areas and the development of safer, more effective
substitutions for older products. New applications include diseases
involving poorly immunogenic antigens such as polysaccharides or
populations, such as the elderly, whose immune systems have deteriorated
so that they do not respond to traditional approaches. New therapeutic
products for treating people with diseases such as chronic hepatitis
infection, malaria, acquired immune deficiency syndrome ("AIDS") or
various cancers where a CTL response is thought to be essential may be
possible using the Stimulon(TM) adjuvants.
Aquila's product development programs include the Quilimmune(TM) human health
products and the Quilvax(TM) products for animal health. Phase I clinical
trials of the Company's lead product, Quilimmune-P(TM) for preventing
S. pneumonia infections in people over the age of 65 years, have been
completed. Phase II trials have been initiated. Aquila's lead animal
health product, Quilvax-M(TM) for controlling bovine mastitis has undergone
extensive testing in bovine immunogenicity and challenge trials. The
Company plans to initiate formal USDA licensing trials shortly. A third
potential product, to help control malaria infections incorporating the
antigen SPf66 and QS-21 is in Phase I clinical trials. The Company's
corporate partners are SmithKline Beecham p.l.c., Wyeth-Lederle Vaccines
and Pediatrics, a business group of Wyeth-Ayerst International, Inc., a
subsidiary of American Home Products Corporation, Pasteur Merieux
Connaught, Progenics Pharmaceuticals, Inc., VaxGen, Inc., Virbac S.A. andNABI.
SCIENTIFIC BACKGROUND
The human immune system is made up of several different cell types
including antigen presenting cells ("APCs"), B cells and T cells. In
general, the role of APCs is to process protein antigens from pathogens
such as viruses, bacteria or parasites into smaller fragments and to
present the resulting peptides to T-cells. Antigens can be processed by
APC's through one of two pathways, the Class I or Class II pathway.
Peptide fragments from antigens processed through the Class I pathway are
displayed on the surface of the APC by an immune system protein called the
MHC Class I protein and typically result in a cellular immune response.
Those processed by the Class II pathway are displayed by MHC Class II
proteins and typically result in a humoral response. When a humoral
response is stimulated, B cells are activated by a specific type of T
cell, called a helper T cell, to produce antibodies which are specific for
the antigen encountered. Two populations of T-helper cells have been
identified, Th-1 and Th-2. T-helper cells secrete biologically active
molecules called cytokines, which mediate the effects of immune system
cells. Th-1 and Th-2 T-helper cells secrete different types of cytokines
and promote the synthesis of different classes of antibodies. The
antibodies produced by B cells will bind to and can neutralize the
pathogens - bacteria, parasites and viruses - which have invaded the body.
In the cellular response, a second type of T cell, called a cytotoxic T
lymphocyte (CTL) is activated. These cells recognize and kill cells
containing pathogens. T-helper cells and the cytokines they produce are
also important in generating a CTL response. The specific activation of
cytotoxic T cells, called a CTL response, is thought to be very important
in products designed to treat or prevent diseases such as herpes,
hepatitis, HIV and malaria. It is also thought to be critical for many
immunotherapeutic approaches to the treatment of cancer.
Traditional approaches for developing immune protection from infection in
humans involved the use of animal viruses, or the use of attenuated or
killed pathogens as vaccines. For example, the injection of cowpox virus
protects humans against smallpox infection. Vaccines to protect against
polio have been developed using either attenuated or killed polio viruses.
While these approaches are effective, there is a small but significant
risk of disease developing in people receiving these types of vaccines.
With the advent of recombinant technology, scientists realized that safer
products could be created, using specific components of an organism rather
than the whole organism. For example, the genes for the surface antigens
from a pathogen can be cloned using genetic engineering and used to make
recombinant proteins. The recombinant proteins are then used in a
vaccine, to make a so called sub-unit vaccine. Other specific components
have been used to stimulate disease specific responses, including proteins
isolated from the pathogen itself, synthetic peptides, carbohydrates and
lipoproteins.
When these newer technologies were first used, it was found that while a
pathogen specific immune response was stimulated, often this response was
not of the right quality or strong enough to provide protection from
infection or disease. As a result, immune modulation technologies have
been developed that are coupled with pathogen specific antigen approaches.
These methods for modulating the immune system include conjugation of the
antigen to a carrier protein, the use of viral or bacterial vectors to
carry specific genes, the use of cytokines or lymphokines to stimulate the
immune system and the use of adjuvants. Carrier proteins such as keyhole
limpet hemocyanin (KLH) or the toxoids from diphtheria, tetanus and
cholera have been used effectively. An example of this type of vaccine is
the Haemophilus influenzae type b conjugate vaccine, such as HibTITER(TM)
sold by Wyeth-Lederle Vaccines and Pediatrics, where the antigen is
conjugated to a diphtheria protein. Viral vectors such as vaccinia,
canary pox, or the bacteria BCG are under evaluation as carriers of
disease specific genes to determine whether they stimulate a protective
immune response. Adjuvants that have been used or which are in
development include aluminum hydroxide (Alum); MF59, a product of Chiron
Corporation and its affiliates ("Chiron"); monophosphoryl lipid A (MPL), a
product of Ribi ImmunoChem Research, Inc. ("Ribi"); LeIF, a product of
Corixa Corporation ("Corixa"); and saponins from Quillaja saponaria such
as QS-21. These adjuvant technologies are not all the same, affecting the
humoral and cell mediated pathways differently. Some approaches result in
general immune stimulation. Others are more specific. Aquila is
developing the Stimulon(TM) family of saponin adjuvants (QS-21, QS-7) as an
immune modulation technology. The Company uses biotechnology approaches
for the creation of specific antigens, and combines these with the
Company's proprietary Stimulon(TM) adjuvants to develop safe and effective
products.
With the advent of new technology, changes are occurring in the market for
immune modulating agents. Because development of these new products
involves a high rate of technological innovation, it is possible to
protect new products through patenting, which can result in increased
profit margins. While product liability costs are high for traditional
vaccines (because of the safety concerns), product liability costs for
products using the new technology are comparable to those for therapeutic
products. Manufacturing costs can be lower for new immune modulation
products than for other therapeutic products. In the manufacturing of
recombinant therapeutic enzymes it is often difficult to retain the
enzymatic activity, and this can limit the choice of manufacturing
methods. The limitations are not so stringent for products used to
modulate the immune system. Historically, vaccines were generally low
priced because the products were used to prevent disease in healthy people
(prophylaxis) and, due to the lack of product differentiation, companies
generally competed on price. However, in today's approaches to disease
management and with the new proprietary innovations, immune stimulation
products have been recognized as very effective contributors to
controlling the total medical costs of certain diseases. Therapeutic
products involving immune stimulation are in development for a number of
intractable diseases, as are products for populations beyond infancy -
young adults and the elderly.
The Use of Adjuvants: Technology to Enhance the Immune System
Adjuvants are agents which are added to a product to improve or adjust the
immune response. Alum is the only adjuvant currently used in human
vaccines licensed by the FDA. This adjuvant probably acts by a depot
effect, which means that the addition of alum to a vaccine causes the
antigen to remain at the site of injection for a longer period of time,
which seems to increase the humoral immune response. Another adjuvant
under development by Ribi is a mixture of lipopolysaccharides derived from
bacterial cell walls, and is called MPL. Its use can increase the level
of antibodies that are produced in response to an antigen, but additional
components are often required to stimulate a significant CTL response.
Chiron is developing an adjuvant called MF59 which is an emulsion of three
lipids and water. It is a general, broad immune stimulant which will
activate the immune system in the absence of an antigen. Oil/water
emulsions have been used in older vaccines and also act by a depot effect.
Corixa is developing LeIF, a protein produced by the parasite Leishmania,
which is believed to stimulate certain APCs. Aquila's Stimulon(TM) family of
adjuvants, QS-21 and QS-7, are purified, defined molecules, isolated from
natural sources. They stimulate antigen specific responses and have been
shown to promote both antibody and CTL immune responses in animals.
AQUILA'S CORE TECHNOLOGY
Aquila and its corporate partners are developing new products based on two
core technologies: (1) the Stimulon(TM) family of adjuvants that
specifically enhance antibody and CTL responses; and (2) proprietary
antigens that are specific for the target disease.
The Stimulon(TM) Family of Adjuvants
QS-21 is the lead Stimulon(TM) adjuvant. It is a natural product, purified
from the bark of a tree which grows in South America, called Quillaja
saponaria. Up to 10% of the bark from Quillaja saponaria is composed of
saponins of which QS-21 is typically one of the more prominent. The bulk
bark extract is available in the United States. The Company believes QS-
21 is well-suited to pharmaceutical development and formulation because it
has good stability as a dried powder (at least 3 years), is water soluble,
and, when rehydrated, is a clear liquid that mixes easily with other
vaccine components. QS-21 is compatible with Alum and microparticles
which are used in many experimental product formulations. QS-21 is well-
characterized with a known molecular structure - distinguishing it from
competing adjuvant candidates, which are typically emulsions or
biologicals. Because QS-21 is currently regulated by the FDA as a
"constituent material" used in drug preparation, the FDA does not require
licensure of facilities used for its manufacture. A second Stimulon(TM)
molecule, QS-7, which has a slightly different safety and activity
profile, is in development. Patents have issued to Aquila with
composition of matter claims covering QS-7 and QS-21, as well as two other
identified saponins, QS-17 and QS-18. The Company has also been issued a
patent for chemically modified saponins. All patents include the use of
all of these molecules as adjuvants. See "Patents and Proprietary Rights"
and "Risk Factors".
The use of Stimulon(TM) adjuvants improves the quality of the immune
response. Addition of QS-21 to antigens will generally broaden the type
of antibody produced and stimulate cell mediated responses. The quality
of these responses is important for the development of effective products.
QS-21 also produces a strong quantitative response; that is, higher
antibody levels are achieved. It is potent and active at microgram doses.
QS-21 increases the titer, or amount, of antibodies produced by the immune
system in response to vaccination with many types of antigens, including
recombinant proteins derived from viruses and bacteria and free
polysaccharide antigens from bacterial pathogens. An unusual property of
QS-21 not shared by other adjuvants is its ability both to increase
significantly the antibody response to free polysaccharide antigens and to
boost the titer further with a subsequent vaccination.
QS-21 broadens the antibody profile by promoting both Th-1 and Th-2
dependent immune responses. The type of protective immunity elicited by
an infection with a virus or bacterium typically includes antibodies of
several isotypes (also called classes and subclasses). Some of these
isotypes can be more important than others in mediating protection against
viral or bacterial pathogens. Vaccination with a recombinant antigen
typically stimulates only a few isotypes. Some adjuvants, such as Alum,
also only stimulate a narrow range of antibody isotypes. Hence, alum may
stimulate a high quantity, but a lower quality, antibody. In contrast, QS-
21 stimulates high quantities of a broad range of antibody isotypes,
enabling the antigen-induced antibody response to resemble natural
protective immune responses.
QS-21 also stimulates cell-mediated immune responses and induces the
production of cytotoxic T-lymphocytes. The CTL response is a critical
means of natural defense against viral infections and, is believed to
eliminate abnormal cells that might otherwise develop into cancer. Until
recently, it was generally thought that recombinant antigens could not be
used to elicit CTL responses. Alum and simple oil/water emulsions
typically fail to induce CTL responses. However, Company scientists
discovered that the simple addition of QS-21 to these antigens stimulates
the production of a CTL response to the recombinant antigens in animal
studies. Other investigators have also reported that CTL responses
induced by recombinant vaccines adjuvanted with QS-21 can mimic the
protective CTL responses induced by viral infection.
The Company believes that the performance of QS-21 will vary depending
upon the nature of the antigen and the target population. Initial human
studies conducted by the Company's licensees and collaborators have
focused on proving the safety of QS-21 and experimenting with different
formulations and dose levels. Aquila and its collaborators have completed
24 studies to date; an additional 24 studies are underway and over 1300
subjects have received QS-21 in various different formulations. These
studies have shown that the addition of QS-21 to product formulations
improves the immune response to certain antigens, as evidenced by
increased antibody titer. No serious adverse events attributed to QS-21
have occurred thus far in the clinical studies. Some local reactogenicity
which is thought to be due to the enhanced immune response and some pain
on injection have been seen in certain vaccine formulations. The Company
has recently completed initial human clinical trials of a new formulation
of QS-21 which it believes will reduce the pain on injection seen in these
particular vaccine formulations.Disease Specific Antigens
Aquila's ability to develop and produce proprietary disease specific
antigens allows it to develop products targeted at specific applications
and populations. Company scientists have scientific expertise in: (1)
recombinant DNA cloning methods; (2) mammalian, insect and bacterial cell
expression; (3) extraction and purification of compounds from natural
sources and (4) carbohydrate and polysaccharide production. Furthermore,
Company scientists have demonstrated their expertise with a variety of
antigens from both viral and bacterial pathogens including those that
require high level biocontainment (i.e. BL-3). These antigens include the
envelope protein from feline leukemia virus, two outer surface proteins
from Borellia burgdorferi, fibronectin binding proteins from
Stapholococcal aureus, and a variety of cell surface proteins from
granulocytic Ehrlichia.
The typical development pathway for a disease specific antigen includes
antigen identification, preparation of research quantities of the antigen,
demonstration of a biological effect of a product containing the antigen
and development of commercial scale antigen production procedures. These
developmental efforts can include those primarily accomplished within the
Company or technology licensed by the Company from outside sources, or a
combination of both approaches. This pathway has been completed for the
feline leukemia virus and B. burgdorferi antigens, is nearing completion
for the Staphylococcus aureus ("S. aureus") antigen and is at an early
antigen identification stage for those from Ehrlichia. The Company has
research ongoing on the production of S. pneumonia polysaccharide antigens
by fermentation and purification.
The Company attempts to protect its antigen technology either through
maintenance of trade secrets or filing of patent applications. U.S.
patents have been issued covering the Company's FeLV(TM) and S. aureus
antigen technology as well as its baculovirus expression system. In
addition, patents have been filed which address antigens from B.
burgdorferi and Ehrlichia. However, there can be no assurance that
patents will issue from the patent applications or that if issued such
patents will not be challenged or that the rights granted under any issued
patents will provide adequate proprietary protection. In certain cases
the Company has licensed proprietary technology covering specific antigens
from third parties. See "Patents and Proprietary Information," and "Risk
Factors".AQUILA'S STRATEGY
Aquila's objective is to create and commercialize products which modulate
the immune system to prevent, control or treat infectious diseases and
cancers. The Company's strategy is to exploit its expertise in adjuvant
and antigen research, to create products and develop them through FDA or
USDA licensure, to support its corporate partner's product development
programs, to develop its manufacturing capacity, and to in-license and
develop related technology.Exploit Expertise in Adjuvant and Antigen Research
Aquila has developed unique expertise in understanding the role of
adjuvants in stimulating and tuning the immune response to specific
antigens to allow the development of safe and effective therapeutic and
prophylactic products. The Company intends to continue to integrate its
proprietary core technologies and to identify targeted applications of its
technology. In addition, the Company plans to broaden its expertise in
research and development involving different antigens including
recombinant proteins, peptides, polysaccharides and other classes of
antigenic molecules. Aquila's strategy is to acquire related products and
technologies to supplement its scientific expertise, its capabilities and
its product portfolio.Create and Develop its Own Products
Aquila has established a large number of corporate partnerships and a
significant number of products are being developed through these
partnerships. However, Aquila believes that it can develop and retain
significant value through its own product development efforts. The
Company has three products in clinical development: (i) Quilimmune-P(TM) for
preventing pneumococcal infections in the elderly for which Phase I trials
have been completed and Phase II trials commenced recently; (ii) Quilvax-
M(TM) to control bovine mastitis for which immunogenicity and challenge
trials have been completed; and (iii) Quilimmune-M(TM) for controlling
malaria, which is in Phase I trials. Aquila has research ongoing with
other potential adjuvants and on the discovery and development of antigens
for tick borne diseases. The Company has completed the development and
licensure of one product, Quilvax-FeLV(TM) for preventing leukemia in cats.
See "Aquila's Product Development Programs".
Aquila has a large number of academic collaborations ongoing involving
other antigens. A number of these involve cancer vaccines. In certain
cases the Company has options to license related technology should it wish
to accelerate the development of these products. The Company intends to
develop human products primarily but will exploit unique, significant
product opportunities in animal health.Support Corporate Partners Programs
Aquila has entered into collaboration agreements with SmithKline Beecham,
p.l.c., Pasteur Merieux Connaught, Wyeth-Lederle Vaccines and Pediatrics,
VaxGen, Inc. NABI and Progenics Pharmaceuticals, Inc. as well as a number
of other biotechnology companies. Aquila intends to leverage these
partnerships to speed discovery and development of certain products which
the Company does not have the resources or skills to develop. These
collaborations allow the Company to focus its own efforts on products
which have different markets than those of interest to large
pharmaceutical companies. The Company has a number of potential licensing
discussions underway and intends to continue to selectively license its
technology. See "Corporate Partner Programs".
Continue Developing Manufacturing Capacity
Aquila has retained rights to the manufacture of QS-21 on a worldwide
basis in all of its licensing agreements, and has been producing QS-21 for
clinical trials for all of its partners and its product programs. In
addition, the Company operates a small manufacturing facility to supply
FeLV antigens and vaccine to its corporate partner Virbac S.A. Aquila has
produced commercial scale quantities of its canine lyme product and has
the capacity to produce specific commercial requirements of its Quilvax-M(TM)
product for bovine mastitis. Aquila intends to continue to develop
manufacturing expertise and capacity to allow it to retain value from the
products which it develops.
[more in next post] |
