Raven's integrated technology platform rapidly generates a continuous supply of well-characterized, high-affinity monoclonal antibodies to proteins on the cell surface that can be used to quickly identify and validate targets—creating an optimal starting point for developing a new drug.

Human Tissue-Specific Progenitor Cell and Human Tumor-Derived Cell Lines Generated by Raven: A Rich Source of Novel Antigens

The keystones of Raven's approach are the human tissue-specific progenitor cell lines and cancer- stem cell lines we have developed specifically to serve as antigen sources for raising monoclonal antibodies for a variety of cancers. These new types of cell lines, never before grown in the laboratory, provide Raven with an entirely new class of biologically relevant antigen sources for drug targets. To date, we have developed 30 proprietary cell lines including progenitor cells from lung, prostate, colon, stomach, pancreas, liver, kidney, and ovary; and cancer lines from sarcomas, ovarian, breast, cervical and prostatic carcinomas, as well as cancers of the lung, colon, liver, and stomach. Raven's cell lines have been proven to generate a much higher percentage of robust, therapeutically useful monoclonal antibodies than conventional cell lines, including "cancer" antigens. Raven has validated its approach by rapidly obtaining functional antibodies to known tumor targets including EGF-R (the target of Erbitux®) and HER2 (the target of Herceptin®).

Efficient Antibody Creation & Selection

Raven uses an efficient method for exploiting the cell lines' characteristics to rapidly raise monoclonal antibodies targeting proteins on the cell surface. Raven's proprietary methods for generating monoclonal antibodies reactive to protein targets on the cell surface consistently yields a much higher percentage of cell surface-directed antibodies (40%-60%) compared with approaches using conventional methods of immunization (<0.1%). In our first screen, we confirm that the antigen is on the cell surface. We then screen for the significantly greater presence of these targets on cancer tissue than on normal tissues. About 90% of antibodies fail these tests and are discarded within the first week. This quickly focuses the discovery process on accessible, cell-surface cancer targets. Raven uses the purified antibodies that have passed the preliminary immunohistochemistry screen in a series of broader screens using a larger number of normal and tumor tissues with frozen and/or fixed samples.

Functional Screening Methods that Accelerate Identification of the Most Therapeutically Relevant Monoclonal Antibodies

After generating and identifying monoclonal antibodies that bind to cell-surface antigens on a chosen cell line, Raven applies proprietary high-throughput tissue screens and "focused proteomics" approaches to assess those proteins' biological function and relevance to disease, rapidly narrowing the candidates to those most likely to be good disease targets. Using our proprietary CellArray™ technology, Raven can, within days, assess the prevalence of the targeted antigen on a large number of cell lines and patient samples. Raven integrates its proprietary high-throughput screens, automated CellArray™ system, and focused proteomics approaches to discard irrelevant antibodies within 7 to 10 days. In contrast, it may take months or years to express, purify protein, and raise antibodies against a target identified in a genomics-based screen.

Core Proprietary Discovery Technologies

The following core tools & technologies drive Raven's discovery platform:

• Progenitor & cancer cell lines
• Immunization methods
• Screening methods (IHC or normal human tissues and tumor tissues)
• CellArray™
• In vivo models for efficacy and toxicity
• Screening for cell-surface binding and internalization
• Flow cytometry
• Bioactivity (cell cycle, apoptosis, oncosis)
• Target identification using proteomics tools

The Power of the Platform

Raven's approach provides distinct advantages not found in other discovery approaches:

A cancer CellArray™ stained for DNA (red) and with an anti-her2 antibody (green) easily identifies her2 overexpressors.

Identification of Targets not Accessible to Other Approaches

Targets that are reachable via genomics and proteomics approaches represent a small subset of total possible cancer targets. By capturing the complexity of the whole cell, vs. just the gene sequence, Raven is positioned to capture the full subset of cell-surface drug targets—including identification of targets that would otherwise have gone undiscovered or may have been easily overlooked using genomics or proteomics techniques—thus expanding the universe of potential treatments.

Multiple Product Development Opportunities

Raven's antibody candidates, which bind to antigens that are present at high levels on tumor tissue but barely detectable on normal tissues, are also ideal for development as therapeutic and diagnostic antibodies in the following formats:

• Delivery of immunotoxins and radionuclides
• Antibodies for diagnostics and imaging
• Protein or small-molecule therapeutics to Raven targets

Accelerated Development Timeline; Decreased Costs

Raven's discovery process makes target validation and drug lead creation simultaneous events, resulting in a far more cost-effective process that shortens the development timeline by three to seven years.

Increased Probability of Success in the Clinic

By focusing on the relevant biological system and using improved animal models to predict safety and efficacy, Raven's approach substantially increases the likelihood of success in clinical trials.

Capability to Deliver Substantial & Sustained Drug Discovery Output

A key distinguishing characteristic of Raven and an important measure of our platform's success is our consistent discovery of novel disease-related targets on the cell surface and creation of unique, biologically active monoclonal antibodies directed specifically against them. From our 30 proprietary progenitor cell lines, we have produced a portfolio of more than 200 potential antibody drug targets during our first four years.

Capability to Generate Targets for All Cancers and Many Other Disease States

Our platform can identify targets and generate monoclonal antibodies for any disease for which diseased tissue can be identified and obtained for screening.