Coming Soon? A New Biologic
For the past two decades, monoclonal antibodies (mAbs) have dominated the biologic drugs market. Doctors use these blockbuster products for a range of diseases, including many cancers and autoimmune diseases. In addition to their effectiveness, mAbs generally produce fewer side effects than traditional small molecule drugs. In the world of pharmaceuticals, biologics have “high specificity.” In other words, they interact only with their intended target. That’s the good news about mAbs.
Despite their therapeutic success, mAbs are not perfect. Their complex structure means that they must be produced in Chinese hamster ovary (CHO) cells rather than bacterial cells, which is significantly more expensive due to the higher cost of CHO cell growth media as well as the longer time required for CHO cells to grow. Monoclonal antibodies are also very large, molecularly speaking—which means that in some instances, they are not effectively able to penetrate their target tissue.
This week, we examine an up-and-coming alternative to the amazing, somewhat problematic mAb: DARPins—Designed Ankyrin Repeat Proteins. This new type of therapy is currently in clinical development and seems to possess many of the advantages of mAbs without the complexity and size. Here’s how.
Disassembling the Protein Puzzle
To understand a DARPin, we need to first think about how proteins are built. Proteins are chains of amino acids—complex, three-dimensional forms that arise from intermediate layers of structure. The most basic level of protein structure is the primary structure, a linear sequence of amino acids that make up the protein.
The secondary level consists of highly regular, local three-dimensional structures within a protein. Secondary structure comes from interactions between neighboring amino acids. Two common types are alpha helices and beta sheets. Regions of secondary structure may group together to form a motif—a pattern that is found in several different proteins.
Alpha-helices and beta-sheets interact to form a complex three-dimensional structure known as tertiary structure, but it is the secondary structures known as alpha helices that form the basis for the newest implement getting ready to emerge from the pharmaceutical toolbox—the DARPin.
The word “DARPin” is an acronym for “Designed Ankyrin Repeat Protein.” An ankyrin repeat is a motif that consists of two helices separated by a loop, as shown below. The number of helix-loop-helix repeats varies from four to thirty-four.
The ankyrin repeat motif is only one of a number of secondary protein structures, but for our purposes, it’s the only one that matters. It mediates a wide variety of protein-protein interactions. The number of repeats present influences the final shape of the motif, and so determines what target protein the ankyrin repeats interact.
Simpler, Cheaper, Faster Protein Power
The founders of Molecular Partners (Zurich, Switzerland) genetically engineered a large library of ankyrin repeat proteins—the aforementioned “DARPins.” These DARPINS are then screened for their ability to interact with and modulate a variety of drug targets, with the same high specificity of mAbs.
DARPins’ structure is far less complex than that of mAbs. Consequently, companies can use bacteria cells to manufacture them—which translates into much cheaper production costs. The relative “simplicity” of DARPins may also mean that researchers will have an easier time formulating them for therapeutic use. And yes, you guessed it, DARPins are also small in relation to mAbs. Their size may enable them to penetrate hard-to-reach targets like solid tumors. These characteristics mean that at least for some uses, DARPins may prove more effective than their bigger biologic cousins. (Article continues below)
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Eyes On DARPins
Molecular Partners’ most advanced DARPin therapeutic, Abicipar, is in Phase III clinical development for wet age-related macular degeneration (AMD), a serious eye condition. Wet AMD is caused by excessive growth in the arteries and capillaries that supply the retina with blood. The overgrowth leads to retinal detachment, which can ultimately cause blindness. Abicipar works by binding to and inhibiting the growth factor, vascular endothelial cell growth factor (VEGF) that triggers the blood vessels’ runaway growth. Molecular Partners is developing Abicipar in partnership with Allergan (Dublin, Ireland).
Molecular Partners also has two clinical candidates in oncology. The first, MP0250 is in Phase II development for multiple myeloma and non-small cell lung cancer. MP0250 is a “Multi-DARPin,” which means that it can recognize two targets at once. This strategy has important implications. Tumors mutate very rapidly, so they often develop resistance to therapies. By targeting two cancer-associated proteins simultaneously, researchers hope to overcome this challenge. MP0250 binds to and inhibits both VEGF and hepatocyte growth factor (HGF). Tumors secrete VEGF to promotes angiogenesis, or the growth of blood vessels that supply nutrients into a tumor. Inhibiting VEGF can help starve the cancer. HGF promotes growth of the tumor cell itself.
The second oncology drug candidate, MP0274, is aimed at HER2-positive breast cancer, a form of the disease that produces extra copies of the HER2 growth-factor receptor protein. MP0274 binds to two different sites on HER2 and induces apoptosis (cell suicide). This mechanism differs from that of the mAb Herceptin. Herceptin also targets HER2-positive breast cancer. However, it binds to a different HER2 site and blocks growth factor signaling. It also activates the patient’s immune system to attack the tumor. MP0274 is in Phase 1 clinical testing for HER2-positive cancers, including breast and gastric cancers.
In partnership with Amgen (Thousand Oaks, CA), Molecular Therapeutics also has a DARPin entering the immuno-oncology world. MP0310 is designed to activate immune cells only in a specific tumor, not throughout a patient’s body. Now in preclinical development, MP0310 features two domains. The first domain recognizes and binds a tumor-specific protein. The other binds CD40, a protein on the surface of white blood cells that activates them. The white blood cells will only activate if the tumor-specific domain is also engaged. This fail-safe restricts the DARPin’s activity to tumor cells, which could limit side effects that occur with treatments that systemically activate the immune system.
DARPINs are still in development. Only time will tell if they will become as effective and versatile as mAbs. We look forward to following the story about what just might be one of the next big things in biotech.