PROLOR Biotech (PBTH) uses a novel, elegant, safe and effective approach to prolonging the half-life in circulation of therapeutic proteins molecules. The method involves adding a naturally occurring peptide, carboxyl terminal peptide (CTP), to the protein molecule. By embarking on this strategy, Prolor is in fact mimicking Mother Nature, which attached CTP to human chorionic gonadotropin (hCG) hundreds of thousands of years ago to extend its life span. hCG is a hormone secreted from conception and throughout pregnancy. It induces uterine changes and is essential for maintaining pregnancy.
The story of the CTP discovery began when Professor Irving Boime of Washington University in St. Louis was investigating hCG. He was intrigued by the fact that this hormone, which is responsible for the existence and expansion of humans on planet Earth, has a life span of up to two days, while the structurally similar luteinizing hormone (LH) is eliminated in only twenty minutes. He decided to unveil the secret behind this difference. Observing the presence of a carboxyl terminal peptide (CTP) on hCG but absent on LH, Professor Boime suspected CTP could be inducing the prolonged duration of hCG. He added the peptide to different therapeutic proteins and waited for the results. To his pleasure, CTP caused dramatic increases in the therapeutics’ life spans, confirming his guess. The professor’s post-doctoral student, Fuad Fares, Ph.D., who worked with him on these findings, licensed the CTP technology from Washington University to a company he founded in Israel in 2001, Modigene Inc. The name was changed to Prolor Biotech in 2009.
The firm secured an exclusive license to apply CTP technology to all human therapeutic proteins and peptides, except four endocrine proteins – luteinizing hormone, follicle stimulating hormone, thyroid stimulating hormone, and hCG – that had already been licensed to a firm later acquired by Merck. It also secured the rights to sublicense the technology.
Using conventional techniques for transforming protein therapeutics into nontoxic, non-immunogenic, long-acting medicinals has proven difficult and complicated. Modification of the original molecules can induce additional adverse effects, such as immune responses against the drugs, rendering them inactive or instigating potentially life-threatening hypersensitivity reactions.
For example, attaching large polymeric chains creates very large therapeutic proteins, which can impede the receptor-binding action of the molecules, preventing or reducing their desired effects. Adding carbohydrate structures (glycosylation) to natural proteins can produce potentially toxic molecules. The successes of the conventional technologies have been achieved primarily with endogenous large proteins. Yet, some of the marketed modified protein drugs have diminished biological activity, requiring larger concentrations than those of the unmodified proteins.
The conventional methods have been tried on a large numbers of therapeutic proteins, but very few have reached the market, which is unfortunate, because creating long-acting protein therapeutics is a necessity. The success of many of the protein therapeutics depends on the presence of stable levels of these molecules in the patient’s bloodstream, which is difficult to achieve with molecules having short half-lives. Some drugs that were expected to wipe out viruses or shrink cancers failed in clinical trials, probably because of their short half-lives. Additionally, patients often fail to comply with chronic treatments that must be taken frequently. For those who are compliant, the treatment is a burden to the patients, negatively impacting their wellbeing, especially children.
Prolor’s CTP advantages over the conventional methods include attachment to a wide array of existing therapeutic proteins, stabilizing them and greatly extending their life span in the bloodstream without additional adverse effects and with no loss of biological activity. Moreover, CTP-modified therapeutic proteins have been easy to manufacture through conventional recombinant DNA techniques in mammalian protein expression systems. Importantly, CTP has shown to be potentially non-immunogenic to humans when attached to other proteins.
This small, fascinating peptide, CTP, is elegant, safe, and effective. It offers a simple solution to many important unmet medical needs. The question is: Will CTP work? A proof of concept is already in hand with approval of therapeutic follicle stimulating hormone (FSH), one of the four products Merck marketed through its sublicensing of CTP technology. Phase 3 clinical trials on FSH-CTP have shown no adverse effects, no toxicity, and no immunogenicity. The results have also demonstrated that one injection of FSH-CTP achieved the same pregnancy rates as in women receiving seven consecutive daily injections of FSH. On January 28, 2010, the European Commission (EC) granted Merck marketing approval with unified labeling valid in all European Union member states for FSH-CTP, now branded Elonva®. Is this not the proof of concept we have long been awaiting? Here it is.
MOD-4023: hGH-CTP: This human growth hormone (hGH) therapeutic was recently granted FDA orphan designation. hGH is used for long-term treatment of children with growth failure due to inadequate secretion of endogenous growth hormone and for other reasons. Patients currently using hGH receive 4-8 IU per week divided into 2 doses per day 6 days a week, which is burdensome for pediatric patients. Phase 1 study results suggest that two monthly injections of hGH-CTP are safe and efficacious.
MOD-9013: IFN ß-CTP: Interferon ß (IFN-ß) therapeutic protein reduces the frequency and severity of relapses in multiple sclerosis patients. Study results show that CTP-modified IFN-ß prolonged the half-life of INFß by 13-fold, and overall drug exposure (AUC) in primates by 55-fold. It also demonstrated expanded biological potency consistent with results from a previous study of human melanoma tumors implanted in nude mice. The results demonstrated that IFN ß-CTP induced 100% inhibition after eight days and 87.5% inhibition after 10 days, versus 50% inhibition with commercially available IFN-ß after eight days and just 12.5% inhibition after 10 days.
Prolor Biotech’s program also includes:
MOD-7023: EPO-CTP: Erythropoietin (EPO) is one of the recombinant proteins that made Amgen’s fortune. It is indicated for individuals with chronic kidney failure, chemotherapy patients, and HIV/AIDS patients on AZT, as well as for patients who may require a blood transfusion or undergo surgery where blood loss is expected.
MOD-5023: FVII-CTP: Factor VIIa is currently marketed for bleeding episodes in hemophilia A or B patients.
MOD-1002: OBES-CTP: Prolor believes it can fill a void in the treatment obesity.
MOD-1001: GLP-1-CTP: The GLP-1 therapeutic peptides maintain healthy blood sugar levels and control appetite. Specialized intestinal endocrine cells secrete GLP-1 after meals in response to food intake. The molecules control the body’s glucose levels by stimulating the release and synthesis of insulin, reducing glucagon secretion, and mediating appetite. GLP-1 triggers a feeling of satiety in the brain.
Many proteins are good candidates for half-life prolongation through Prolor’s CTP approach. For example the Fab antibody fragments, i.e. the targeting segments of monoclonal antibodies, have exceptional target-binding affinity and specificity. They can be attached to various drugs for selected biological targets but have not been useful in this respect because of their very short half-lives. CTP technology could enable them to become important therapeutic alternatives to monoclonal antibodies.
Another good example is prourokinase, a thrombolytic therapeutic protein that has the potential to be faster-acting with fewer side effects than the current thrombolytic options tPA, urokinase and streptokinase. The problem with prourokinase is also its short half-life (8 minutes), which means that it must be administered very close to the clot via a catheter threaded through an artery. Developing a CTP-modified prourokinase would enable doctors to inject the hormone intravenously, achieving the same effect with far less cost and complexity.
Plenty of peptide-based therapeutics have short half-lives. Important therapeutic versions of somatostatin, vasopressin, platelet aggregate inhibitors, calcitonin, and immunopeptide have very short durations of action and require daily injections. All these products could be turned into medicines friendlier to the patients.
Are you still wondering if this technique can generate big revenues? Take a look at what the few modified protein blockbusters: Schering-Plough’s PEGIntron, Roche’s Pegasys, Amgen’s Neulasta and Aranesp.