APC Targeting Technology™

THE NEXT GENERATION OF ANTIBODY THERAPEUTICS

Celldex's proprietary technology platform uses fully human monoclonal antibodies administered directly to patients to target dendritic cells and macrophages -- key cells within the immune system. To generate an effective immune response, a vaccine needs to be taken up and processed by these cells, which are also known as Antigen Presenting Cells or APCs. Our recombinant antibody vaccines are designed as off-the-shelf products that enhance the efficiency and effectiveness of vaccination by targeting the vaccine to APCs in the body. Our product candidates using the APC technology include CDX-1307, which is currently in two Phase I clinical trials for multiple cancers. Additional new product candidates are planned to enter clinical development for oncology and infectious disease.

The body's immune system is tasked with recognizing and combating cancer cells, viruses, bacteria and other disease-causing organisms. This defense is carried out mainly by white blood cells and their specific subsets, T-cells, and B-cells, which mediate cell-mediated immune responses and antibody-based immune responses. Professional antigen presenting cells or APCs (including dendritic cells and macrophages) are additional subsets of white blood cells that are critical to the development of specific immune responses. Our APC Targeting Technology™ uses human monoclonal antibodies to deliver a disease target or antigen directly to APCs. Our mAbs are specific for receptors located on the surface of these APCs which are known to be entry portals for antigen processing pathways. In vivo, the antigen attached to the antibody is specifically delivered to the appropriate processing pathways in APCs, particularly dendritic cells (often referred to as "professional" antigen presenting cells). APCs internalize these targeted antigens into specific cellular compartments and then present the processed antigen on the cell surface, thereby initiating the desired immune response.

Our APC Targeting Technology™ has been designed to allow us to take advantage of many important characteristics of human monoclonal antibodies, including their long circulating half-life, well known safety profile, and standardized manufacturing procedures. We believe that our APC Targeting Technology™ provides significant manufacturing, regulatory and other practical advantages over patient-specific and other immune-based treatments and can substantially reduce the dosage and cost currently required in conventional immunotherapies.

Preclinical studies have demonstrated that our APC Targeting Technology™ is able to deliver an antigen in a manner that results in significantly more efficient processing and presentation by APCs than a non-targeted antigen. We believe this creates a more potent immune response than standard sub-unit peptides used in competing immunization strategies. It has been demonstrated in model systems that the antigens delivered by our proprietary monoclonal antibodies are processed and presented by human dendritic cells at least 100 to 1,000 fold more efficiently than a non-targeted antigen. Furthermore, using animal models, we have shown the effectiveness of this strategy in protection against tumor challenges. In addition, using in vitro methods with cells from cancer patients, we have demonstrated that our product candidates can elicit antigen-specific activated T-cells that killed tumor cells expressing the antigen but spared cells lacking the antigen. CD4, or helper T-cells, were also elicited. We believe that activation of these cells are critical for enhancing both humoral and cellular responses, and that these results strongly support our prospects for developing numerous clinical candidates in the coming years.

Our studies, and those of other investigators, clearly indicate that this APC targeted approach induces rapid and significantly heightened immune responses in vivo as compared with non-targeted agents. Importantly, we believe that by effectively targeting antigens to dendritic cells in vivo, our product candidates can transform weakly immunogenic antigens into viable targets for immunotherapy.

In addition to APC-targeted immune stimulating products, we are also exploiting our human APC-targeting monoclonal antibody approach to develop therapeutic modalities for delivering antigen-specific immune suppression approaches for autoimmune and allergic diseases.

Allergic diseases are a variety of pathologies driven by poorly regulated, Th2 type immune responses to foreign, usually non-infectious, antigenic materials (allergens) in the environment. Autoimmune disease on the other hand involves aberrant immune responses to self antigens. The pioneering experiments of Ralph Steinman, Michel Nussenzweig and colleagues at The Rockefeller University, New York have shown that antigens delivered to dendritic cells (DC) in vivo in the absence of a DC activating stimulus, using antibodies to the DC marker DEC-205, induce antigen-specific tolerance. Using this approach they have also shown that such tolerance induction protocols are effective in models of multiple sclerosis and type I diabetes. Others have also shown that targeting antigens to other APC receptors (e.g. Fc receptors) is also able to induce tolerance. Although our programs for this application of the APC technology are early in development, they may lead to new therapies for a broad range of diseases including rheumatoid arthritis, multiple sclerosis, type I diabetes, systemic lupus erythematosus and major allergies.

Celldex has developed proprietary product candidates based on human monoclonal antibodies to the following APC receptors:

• The Mannose Receptor: The mannose receptor (CD 206) is a member of the C-type lectin receptors (CLR) and is abundantly expressed on immature dendritic cells and macrophages. The mannose receptor has a natural role in antigen processing and presentation. The mannose receptor may be uniquely effective at accessing the MHC class I presentation pathway, which is important for generating killer T cells that can directly destroy cancer or infected cells. The first product candidate using a human antibody to target mannose receptors is CDX-1307 a vaccine targeting the tumor-associated antigen, human chorionic gonadotropin β-chain (hCG-β) to the mannose receptor with the human mAb B11. CDX-1307 is currently in Phase 1 clinical development in late stage cancer patients.
• The DEC-205 Receptor: DEC-205 (CD205) is part of the mannose receptor family, but is expressed on distinct dendritic cell populations. The pioneering work of Drs. Ralph Steinman and Michel Nussenzweig at The Rockefeller University, New York has demonstrated that this receptor may be exceptionally effective for APC targeting using models of cancer, infectious disease and autoimmune disease. The first product candidate using a human antibody to target DEC-205 receptors is CDX-1401 a vaccine targeting the tumor-associated antigen, NY-ESO-1 to DEC-205 receptor with the human mAb 3G9. CDX-1401 is expected to initiate clinical development in 2009. Additional programs targeting DEC-205 for vaccination against HIV and other diseases are also in preclinical development.
• The Type I Fc Receptor: The Type I Fc receptor (CD64) is expressed on many antigen presenting cells including dendritic cells. Fc receptors have a natural role in mediating immune responses. Targeting antigens to CD64 on human monocytes, macrophages or dendritic cells has been demonstrated to enhance the efficiency of T cell activation by 100-fold or more. Product candidates using a human antibody to target Type I Fc receptors are being investigated in proof-of-concept models.

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