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Therapeutic Platforms: Cancer, HIV, Autoimmune Disease and Transplantation
The Challenge of Cancer: Individual
Cancers and Mutations
Every individual´s cancer is unique. Therefore, the most effective treatment
is one customized to a particular cancer´s genetic configuration.
Genetic mutations and chromosomal abnormalities are commonly associated
with human cancers. Unfortunately, since the genetic mutations leading
to the development of cancer are often random events, every patient's
tumor can contain a unique repertoire of antigens. This characteristic
of human cancer requires that each patient's immune system be able
to recognize and target the specific antigens present.
To address the challenge of
the unique genetic profile of each cancer and the genetic mutations of
that cancer, Argos´ Arcelis personalized immunotherapy technology for cancer
captures the complete, unique genetic information of individual tumors, loads a patient's own
dendritic cells with the total tumor RNA and uses these dendritic cells to trigger an appropriate
immune response. The Arcelis immunotherapy for cancer, is therefore, customized to
the unique antigenic repertoire of each patient´s tumor, equipping the
immune system to recognize and fight that particular disease. This approach precludes the need
to identify or isolate specific tumor antigens and enables
targeting of unknown tumor antigens and treatment of patients from whom
only a minute amount of tumor material can be obtained.
Creating a Personalized
Cancer Product
Argos’ Arcelis immunotherapy for cancer starts with precursors of
the patient´s dendritic cells, which, when matured for the immunotherapeutic,
are currently considered the most effective antigen-presenting cells within
the immune system. Argos amplifies whole tumor RNA from each individual patient
(whether from the primary tumor site, distant metastatic sites or from
tumor cells present in circulation) and then transfects the same patient's dendritic
cells with the patient's tumor RNA. This process offers the opportunity for
most cancer types at any stage of disease to be target opportunities for
the Company's cancer immunotherapy approach.
Unique Advantages
- Dendritic cells transfected with RNA-encoding tumor antigens have
been shown to stimulate potent immune cell responses equal or superior
to other competing approaches
- The Arcelis immunotherapeutic is completely autologous (derived from the
patient’s body), potentially offering maximum safety with minimal
side effects
- The Arcelis immunotherapeutic targets the entire antigenic repertoire of
the tumor including ‘private mutations’ unique to that
patient
- A single production run makes enough product to continuously treat
the patient for several years
- Production requires only a minute tumor specimen, allowing treatment
both of earlier stage and later stage patients
- Argos´ centralized, automated manufacturing process is optimized for ‘day-old’ monocytes,
allowing for production that provides the flexibility
to access patients and clinical sites nationwide
- Formulation requires no specialized manipulation at the clinical
sites, maximizing site participation (thaw in vial, load syringe, inject)
HIV & OTHER INFECTIOUS DISEASES
Chronic viral infections, such as those caused by human immunodeficiency
virus (HIV) and hepatitis C virus (HCV), are difficult to treat and often
incurable. Argos is applying its Arcelis technology platform to transfect dendritic
cells with patients’ own viral RNA antigens, promoting immune responses
perfectly matched to the patient’s unique viral variants.
The Arcelis HIV process utilizes small plasma samples from infected patients to amplify
large quantities of messenger RNA that encode selected viral antigens.
This technique has the added advantage of amplifying the multitude of patient-specific
viral variants evolving in the infected patient, allowing for the creation
of a therapy perfectly suited to the individual. Therefore, the viral sequences
presented to the immune system to recognize and attack are completely compatible with the virus
that has infected the host. The simultaneous presence of autologous viral
sequences and dendritic cells should result in a novel immune response, personalized to each patient,
that potentially has a greater probability of success in controlling residual
virus or a rebound of virus following the cessation of therapy.
Studies
published in Nature Medicine and The Journal of Infectious Diseases have
demonstrated how patient-specific immunotherapeutic approaches similar
to Argos´ have the potential to be effective treatment for people
with chronic HIV infection. Additionally, a Phase 1 trial of Argos´ HIV candidate AGS-004, presented at the
2008 International AIDS conference, demonstrated that AGS-004 achieved the trial´s primary endpoint of
induction of T cells response to patient-specific HIV antigens. Click here
In October 2006, Argos was awarded a $21M National Institutes of Health (NIH)
contract to develop its Arcelis HIV immunotherapy platform. In addition to determining
the immunogenicity of the Arcelis HIV product currently in the clinic, the goal of
the five-year contract is to subsequently develop then test in the clinic
even more potent next generation product candidates.
Argos believes its Arcelis technology can also
be used to create immunotherapies for other chronic infectious diseases
that don’t respond to current treatments. Infections such as hepatitis
C virus (HCV) and herpes represent some of the largest and most significant
areas of unmet medical need. In fact, any disease subject to immune surveillance
is potentially addressable.
Unique Advantages
- The Arcelis immunotherapeutic can be comprised of any number of strategically
selected viral antigens (chosen to not adversely affect the biology
of dendritic cells)
- Amplification of viral antigens includes patient-specific dominant
and quasispecies (important for highly mutagenic viruses such as HIV
and HCV)
- Immune responses generated are 100% relevant for that patient
- Production requires only a small plasma sample that can be obtained
during leukapheresis
- If virus escape occurs at some point post-treatment, the product
can be ‘updated’ using a new plasma sample
- Argos knows of no other dendritic cell-based technology that could
feasibly produce an autologous anti-viral immunotherapeutic
Programs in transplantation and Inflammatory and autoimmune disorders
In addition to its Arcelis technology, Argos has leveraged its expertise in the biology of dendritic cells to develop
additional novel technologies with applications for transplantation rejection
and inflammatory and autoimmune disorders.
The Company is developing a soluble recombinant protein — CD83 — shown
to be an effective immunosuppressant in several mouse model systems. Dendritic cells
treated with CD83 are able to induce regulatory T cells, which are responsible for
immune tolerance to foreign or self-antigens, illustrating the protein’s potential
applications to inflammatory and autoimmune diseases and transplantation rejection.
Preliminary data suggest that CD83 can be developed to treat multiple sclerosis, irritable bowel disease and transplantation rejection. Strikingly,
CD83 distinguishes itself from immunosuppressants, whether FDA approved
or in development, in that it does not appear to require chronic administration
and does not leave the patient globally immunosuppressed.
In February 2005,
Argos received a $1 million grant from the Alliance for Lupus Research
to develop a monoclonal antibody-based therapy for the treatment of systemic
lupus erythematosis (SLE). Argos identified and validated a molecular
target — Interferon-alpha — as a trigger
for the onset and maintenance of SLE, and as having a role in the onset
of psoriasis. Argos is currently testing an anti-Interferon-alpha monoclonal antibody in a phase 1 clinical trial in SLE patients.
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