Monoclonal antibodies have revolutionized the treatment of many diseases by targeting specific disease-related receptors and pathways. However, monoclonal antibodies have shortcomings as well, such as needing to be injected and causing undesirable immune reactions. Cosmix Therapeutics is working to make the next generation of monoclonal antibody products, based on D-peptides called high affinity ligands (HAL).
The HAL platform combines two technologies—mRNA display and chemical protein synthesis (CPS). The intellectual property for both of these platforms was licensed from Gryphon Therapeutics, a forerunner of Cosmix. Gryphon was designing a synthetic form of erythropoietin, but the company closed in 2005 when it became apparent that competitors would beat them to the market.
Amino acids that make up peptides or proteins occur naturally in the body as L-stereoisomers. Cosmix researchers create more stable D-stereoisomers (mirror images) of amino acids and peptides with their platform.
In the first step, a native L-protein drug target is converted into a D-protein drug target using CPS technology. In the second step, mRNA display technology identifies L-peptides that bind tightly to the D-protein drug target. Then the most promising L-peptides are turned into D-peptides and analyzed for binding to the original L-protein drug target.
The mRNA display technology was developed at Harvard University by Jack Szostak, Ph.D., recipient of the 2009 Nobel Prize for medicine. This method creates up to 100,000 billion protein or peptide molecules that can bind to an immobilized desired target. The large population of diverse sequences generated by mRNA display technology increases the probability of selecting rare and diverse sequences with tailored functions. Promising peptides are improved by evolutionary pressure and repeated rounds of selection cycles. By raising the stringency of the desired properties during multiple rounds of selection, peptides with high affinities to the desired target can be enriched and their mRNAs are cloned and sequenced.
D-peptides can be used widely as biotherapeutic agents. Cosmix’ biotherapeutic discovery programs focus on vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and interleukin-4 (IL-4). VEGF, a 165 amino acid dimer, is well suited for the D-peptide approach. VEGF mediates angiogenesis and is a popular target for oncology drugs and other hyperproliferative disorders such as age-related macular degeneration. The marketed monoclonal antibody Avastin (bevacizumab) targets VEGF.
HAL antagonists of VEGF are furthest along in the Cosmix pipeline. Early results in animal models show that D-peptide antagonists of VEGF block tumor growth, have superior tissue and tumor penetration, and can be given orally. “This is a big advantage,” says Peter Wagner, Ph.D., CEO at Cosmix, who plans to file the company’s first IND application for anti-VEGF agents by the middle of 2010.
The cytokine IL-8 plays an important role in tumor angiogenesis and is elevated in pancreatic cancer, mesothelioma, non-small-cell lung cancer, and melanoma. HALs that block IL-8 could benefit a variety of tumor types as well as atherosclerosis. Several D-forms of IL-8 are being investigated in animal models. Over-expression of IL-4 is linked to exacerbations of asthma. Cosmix scientists are starting peptide selection and affinity studies to identify possible lead antagonists of IL-4.
Cosmix’ mRNA display technology also produces peptides for biopurification processes. Cosmix Molecular Biology, a sister company, offers a service to identify peptides against vaccine antigens, which are then used to purify antigens by affinity chromatography. Cosmix researchers not only identify the best peptide ligands for vaccine purification, but they also develop protocols for extracting vaccines from bacterial cells or lysates. Customers scale up the protocols at their own laboratory facilities. “We have long-standing relationships with big vaccine companies,” says Dr. Wagner.