In the quest for new biotechnology drugs, the Holy Grail is a drugmade from a small molecule that performs the same role as a largerprotein like an antibody or cytokine. As sought after as they are, suchmolecules have remained elusive.
CDR Therapeutics Inc., of Seattle, said it has a strategy that just mayunearth a few of these drugs. Ron Berenson, president and CEO ofCDR, said his company is trying to create tiny mimics of the businessend of monoclonal antibodies, cytokines and adhesion molecules inorder to treat cancers and autoimmune diseases. "Lately, there havebeen a lot of encouraging data using monoclonal antibodies, but ithas been difficult to overcome the difficulties antibodies present,"Berenson said.
Because monoclonal antibodies bind only to very specific targets,they offer the basis for the seemingly perfect drug. The problem liesin the fact that they are so large _ comprised of approximately15,000 amino acids each. As a result, it is difficult to administer themto a patient in an active form. Monoclonal antibodies also can causesevere allergic reactions because they are such large proteins.
From his work at Stanford University, Berenson was quite familiarwith such limitations and started to look for ways of getting aroundthem. Last November, he met with Mark Greene, a professor ofimmunology at the University of Pennsylvania in Philadelphia.Green, in collaboration with Colorado State University chemistRobert Williams, developed a method for creating small moleculesthat were as active as the monoclonal antibodies they mimicked.
Based on those conversations, Greene and Berenson founded CDR inJanuary.
The technology that CDR now is licensing from Greene and theUniversity of Pennsylvania exploits the natural design of antibodies,cytokines, adhesion molecules and some receptors. These moleculesare part of the immunoglobulin superfamily. All of these moleculesfollow a similar structural motif: subunits of approximately 100amino acids linked together by amino acid loops. As it turns out,these loops, known as complementarity-determining regions, are theactive portion of all of these molecules _ they determine what theantibody or cytokine binds to.
Greene's method allows him to determine which one of the loops isresponsible for the binding. Synthesizing a 5-10 amino acid mimic ofthe molecule which is held tightly into a loop by a proprietarychemical process produces a small molecule that will behavebiologically as the full protein.
"Our hope is that we can eventually produce drugs based onantibodies and other members of the superfamily that can be takenorally or applied topically, and, are more biologically and clinicallyactive than their parent compounds," Berenson said.
CDR is developing a mimic of a Her2/Neu monoclonal antibodywhich stops epithelial tumor growth. Genentech Inc., of South SanFrancisco, currently has a Her2/Neu monoclonal antibody in PhaseIII clinical trials in breast cancer.
"We plan to make mimics of molecules that have already shownbiological activity rather than focus on finding an activity for amolecule [that we have mimicked]," Berenson said.
In addition to cancer, CDR is focusing on creating mimics that quellinflammation like those found in autoimmune diseases andtransplantation. They are designing mimics to antibodies against Tcells as a potential topical therapy for psoriasis. And, they aredeveloping another mimic for use after corrective eye surgery toencourage corneal healing.
All products are in animal testing.
CDR received $6 million in venture capital funding in Septemberfrom The Sprout Group, AltaPartners, Sofinnova and Arch Partners.n
-- Lisa Seachrist Washington Editor
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