April 15, 2006 (Vol. 26, No. 8)

Manufacturing Efficiencies and Drug Delivery Improvements Advance the Field

Fail fast and fail cheap is the current mantra in drug discovery. This approach is based on the premise that elimination of high-risk compounds early in the discovery process increases the success rate of finding a new therapeutic drug. Also, companies are under increased pressure to cut drug development costs and increase productivity. Hence, they are turning their attention to small peptides in their quest to find the next blockbuster drug.

Peptides play an important role in modulating many physiological processes in our body. Some of the benefits of working with peptides are: they are small, easily optimized, and can be quickly investigated for therapeutic potential. However, the field of peptide drug discovery was hampered by their high manufacturing costs, short half-life, and limited in vivo bioavailability. All that is changing now. Waheed Danho, Ph.D., distinguished research leader at Hoffmann-La Roche (www.roche.com), says &#8220Advancements in peptide manufacturing and improvements in peptide drug delivery systems have re-energized this field. It is now easier to screen a large number of targets with peptides and eliminate the unpromising ones early on in the discovery process.&#8220

Rational drug design, an informed approach to drug discovery, is the preferred route for Roche, which has a fully integrated peptide research program based on rational drug design. &#8220The quick-acting nature of peptides is often a disadvantage in many disease conditions. We perform extensive structure-activity-relationship studies to define peptide hot spots and use this information to design more potent, more specific, and more long-acting peptides,&#8220 explains Dr. Danho.

Natural vs. Combichem Approach

Systematic screening of peptides is a well-established approach. The peptides can be naturally derived or chemically synthesized, with the latter method being more prevalent.

Ambryx Biotechnology (www.ambryxbiotech.com) performs systematic screening of naturally derived peptides. It has an anticancer peptide in the preclinical stage with three more in R&D. &#8220We assessed secreted protein fractions derived from embryonic cells for apoptotic effects in multiple in vitro cancer cell models. We discovered a native protein that binds to zinc resulting in a conformation change revealing active peptide domains that have anticancer activity. We subsequently isolated the active peptide domain,&#8220 says Helen Chen, Ph.D., vp of business development at Ambryx.

Ambryx&#180 anticancer peptide drug has natural glycosylation, so it has the potential to last longer in vivo and be truly bioavailable. &#8220The peptide was 8 to 10 times more active than native protein as it does not require zinc for activity,&#8220 says Dr. Chen. The company is currently gathering data in animal obesity models.

Advances in understanding how to modulate peptides have resulted in novel peptides for screening, according to Christopher Holmes, Ph.D., senior director of chemistry at Affymax (www.affymax.com). Affymax leverages its combichem expertise for peptide drug discovery.

The company&#180s four-step process starts by identifying peptides of interest, synthesizing peptide analogs, analyzing both sequence and architecture, and studying effects in animal models of disease. &#8220We use PEGitecture, which is the simultaneous study of architecture and PEGylation, to modulate activity and increase peptide half-life,&#8220 explains Dr. Holmes.

&#8220Our main focus in peptide therapeutics is in nephrology and oncology,&#8220 says Mary Fermi, senior director of commercial development at Affymax. &#8220We are developing Hematide, a synthetic peptide-based erythropoiesis-stimulating agent that stimulates red blood cell production.&#8220

Potential benefits of Hematide include good tolerance, low immunogenicity, simple and less frequent dosing, and sustained increase in red blood cell production, the company says. It is in Phase II trials for the treatment of anemia in chronic kidney disease and cancer and in Phase II dose-finding trial for treatment of anemia in cancer chemotherapy patients.

Peptide Analogs

Zelos Therapeutics (www.zelostherapeutics.com) is developing a novel peptide analog of the parathyroid hormone (PTH) for postmenopausal osteoporosis, called Ostabolin-C (in Phase II trial).

&#8220PTH has two important signaling domains, the first domain activates adenylate cyclase, and the second domain stimulates protein kinase C activity. Studies in in vitro and animal models revealed that the adenylate cyclase signaling component was responsible for the bone-stimulating activity of PTH. We realized that modulating adenylate cyclase had important implications for osteoporosis therapy,&#8220 says Paul Morley, Ph.D., scientific founder and CSO of Zelos Therapeutics.

&#8220Ostabolin-C activates bone-stimulation mechanisms, but does not affect bone resorption activity. Bone resorption leads to the side effects observed with existing injectable PTH drugs. Also, these injectables are more effective at reducing vertebral fractures than fractures of the hip or wrist. We anticipate that our peptide drug will have a lower incidence and severity of side effects and induce the formation of better quality bone at all of these sites,&#8220 says Dr. Morley. Zelos has partnered with Nektar (www.nektar.com) to develop a pulmonary delivery formulation of Ostabolin-C.

The phage-display approach consists of generating peptide phage-display libraries, screening them against targets of interest, and identifying high affinity and specificity target binding compounds. Dyax (www.dyax.com) reports that it successfully used as well as partnered its phage-display technology for peptide drug discovery. Dyax offers linear and constrained loop peptide libraries as tools for peptide drug discovery. The combined diversity of Dyax&#180s constrained loop and linear libraries is reportedly greater than 10 billion each.

Dyax says that use of its phage-display technology often results in novel peptide leads with little to no sequence similarity to any known human sequences. This can be an advantage over natural peptides, which can be highly unstable and have multiple binding partners in vivo. Naturally derived peptides or peptide derivatives are often covered by existing intellectual property or in the public domain. Since phage display derived peptides are often completely novel and large motifs can be generated, it is possible to get strong patent protection around a family of peptide binders.

Intellectual Property

&#8220A big benefit of doing peptide research is IP. Peptides do not have the manufacturing-related royalty stack that exists with antibodies, nor do they require royalties to companies with proprietary vectors, strains, and methods for GMP production,&#8220 says Aaron Sato, Ph.D., senior director of lead discovery.

Two main challenges in using peptide drugs are their short half-life and the need for multiple injections at fairly high doses to maintain activity. CovX (www.covx.com) is developing long-acting biotherapeutics called CovX-Bodies that directly address these issues.

&#8220The CovX technology harnesses the strengths of peptides with the pharmacokinetic advantage of antibodies to create a new molecule called a CovX-Body,&#8220 says Rodney Lappe, Ph.D., CSO at CovX. CovX-Bodies are created in solution by covalently combining a peptide via programming linkers to the binding site of a specially designed antibody. &#8220We can optimize the peptide backbone for potency, selectivity, and half-life by changing linker and tethers on peptides and antibodies. The antibody recognizes only the free end of the tether of the programming peptide molecule and binds at the two Fab sites, resulting in a specific bivalent CovX-Body. We can now finesse the CovX-Body to a half-life ranging from a few hours up to potentially 21 days in humans,&#8220 says Dr. Lappe.

The CovX platform is versatile and can be modified to create effective agonist or antagonists, according to the company. For example, native ligands can outcompete small peptides in disease conditions that require receptor activation. The steric bulk of antibody in the CovX-Body shields the receptor resulting in an effective antagonistic CovX-Body.

A thrombospondin mimetic that stimulates an angiogenesis suppressor mechanism that is critical for retarding vascular growth in tumors is in development. &#8220Our drug requires fewer injections, less peptide dosage (up to10,000 fold less), and exhibits better efficacy compared to native peptides in mouse xenograft models,&#8220 says Bob Mischler, director of commercial development at CovX.

Previous articleASSAY and Drug Development Technologies Editor-in-Chief James Inglese, Ph.D., Director – Biomolecular Screening and Profiling Division, NIH Chemical Genomics Center
Next articleJohn Sterling talks with Bruce H. Littman, M.D., Vice President and Head, Global Translational Medicine, Pfizer Global Research and Development about translational medicine.