Engineered Monothiol Thioredoxin for Treatment of Radiation Induced Lung Injury

Orpro Therapeutics, Inc., San Diego CA

Investigators

Abstract

ABSTRACT This project aims to evaluate if ORP100S, a pre-reduced, monothiol variant of human thioredoxin-1 (TRX) optimized for pharmacology, potency and safety, is able to modulate key inflammatory markers of radiation- induced pneumonitis (RP) and fibrosis (RF) in an in vivo mouse tumor-implantation model as proof of concept for subsequent development as a novel means of mitigating radiation-induced lung injury (RILI). RILI is a common issue for patients undergoing radiotherapy for the treatments of lung cancer and other conditions such as thyroid disease and some blood disorders and manifests acutely as RP and chronically as RF. Radiotherapy is a vital path of treatment for many types of cancers especially solid tumors. The lungs are one of the most radio-sensitive tissues and are prone to damage caused by ionizing radiation, resulting in a significant number of patients being unable to be treated effectively or safely due to RILI, which is a primary dose-limiting factor for radiotherapy, occurring in up to 20% of patients. In mild to moderate cases, where RP or RF have occurred, the patient may be treated with steroids, however, severe cases are often refractory to even high doses. Not only are the resultant medical conditions of RILI potentially severe, the requirement to cease radiotherapy when they occur limits tumor control probability and hence treatment efficacy. OrPro Therapeutics Inc. is developing ORP100S as a recombinant biologic treatment for indications associated with oxidative, inflammatory or muco-obstructive stresses where endogenous TRX activity is limiting. Natural TRX is an essential intracellular human gene product that is also secreted on mucosal epithelia of the lung, upper and lower GI, eye and reproductive tract where it serves a range of homeostatic and protective functions via a unique, selective thiol-disulfide exchange mechanism. ORP100S is a monocysteinic, chemically pre- reduced TRX with engineered mutations including replacement of the second active-site Cys by Ser. These modifications improve stability and activity with excellent safety. Our preliminary studies of ORP100S have demonstrated anti-inflammatory, chemo-protective, radio-protective and mucus modulating activity in vitro, ex vivo and in vivo in animal and human pulmonary disease models. No adverse toxicological effects were observed in mice following acute high-dose intravenous (IV) or subcutaneous (SC) administration. Importantly, ORP100S did not stimulate tumor cell proliferation or reduce chemotherapeutic efficacy. A GMP-ready 15 g/L E. coli manufacturing process and stable ORP100S drug formulation have been established. Our hypothesis is that ORP100S is a safe and effective means of mitigating RILI without affecting tumor killing or treatment efficacy. If successfully developed, ORP100S may be used as a supportive prophylaxis treatment alongside radiotherapy, and could potentially mitigate RILI as a primary dose limiting factor. Ultimately, the increased safety of radiotherapy through the use of ORP100S may facilitate better clinical outcomes by allowing patients to complete a full treatment of radiotherapy without the risk of lung injury.