Heteropolymers: a novel technology against blood-borne infections.

Heteropolymer (HP) technology is a novel cassette technology which is being developed for the treatment of infectious and autoimmune diseases. HPs are dual antibody conjugates, composed of a monoclonal antibody (mAb) directed against the complement receptor type 1 (CR1) on primate red blood cells (RBCs) chemically cross-linked to mAbs that recognize blood-borne antigens. Upon administration of an HP, the target is bound to its counterpart mAb in the HP and immobilized on an RBC by binding of the anti-CR1 mAb to CR1 in a complement-independent manner, forming an immune complex. When the RBC traverses the liver during circulation, the immune complex is recognized by fixed tissue macrophages, the CR1 molecule is cleaved and the HP-pathogen complex is phagocytosed and destroyed. Due to rapid binding and immobilization of the target by HPs, the anti-target mAb used in the HP need not be directed to a neutralizing epitope on the target organism. Studies in animal models have shown that HPs are effective in treating infectious diseases and autoimmune diseases such as systemic lupus erythematosus. HPs are advantageous over natural immune adherence or conventional mAb therapies due to their complement-independent mechanism, low therapeutic dose and lack of the need for neutralizing mAbs against the target.

Evaluation of antigen-based heteropolymer for treatment of systemic lupus erythematosus in a nonhuman primate model.

Autoantibodies that react with double-stranded DNA (dsDNA) are a hallmark for diagnosis of systemic lupus erythematosus (SLE) and are also considered the pathogenic subset that is most associated with lupus nephritis. As an agent to remove the pathogenic dsDNA antibodies from the circulation of SLE patients, we are developing an antigen-based heteropolymer (AHP). The AHP consists of a monoclonal antibody to the complement receptor (CR1) cross-linked to salmon testis dsDNA to effect clearance of anti-DNA antibodies by binding them to erythrocyte CR1. Utilizing a cynomolgus monkey model for SLE in which we infused plasma from SLE patients containing a high titer of high-avidity anti-dsDNA antibody, we have evaluated the safety and efficacy of AHP infusion. The results demonstrate that AHP rapidly (within 2 min of infusion) binds to monkey erythrocytes without causing any toxicological effects. We also demonstrate that human Ig (G+M) antibodies are rapidly bound to the AHP-erythrocyte complex. These events are mirrored in their kinetics by a substantial drop in the level of high-avidity dsDNA antibody in the plasma.