Early Translational III
Advancement in our understanding of stem cell biology over the last decade has provided a tremendous opportunity to pursue regenerative medicines for diseases with unmet medical needs. We plan to accelerate the promise of regenerative medicine by leveraging our experience in conventional antibody drug development to modulate a critical stem cell pathway involved in intestinal tissue regeneration. Crohn's disease and ulcerative colitis, collectively known as inflammatory bowel disease (IBD), affect as many as 1.4 million Americans. IBD is characterized by a chronic relapsing course of diarrhea, abdominal pain, weight loss and rectal bleeding. Direct treatment costs for IBD in US were estimated at $2 billion annually in 1999 while indirect costs may be much higher. Patients struggle with debilitating symptoms for much of their adult life. While several treatment option exist, as many as 60% of patients do not respond to primary therapy or show signs of acute relapse and/or disease progression, indicating a considerable unmet need for more effective therapies. Our promising discovery work has led to a development program to achieve proof of concept for an antibody treatment to drive intestinal renewal in these diseases.
Statement of Benefit to California:
This project will benefit the citizens of California by leveraging experience in conventional drug therapies to realize the potential of regenerative medicine. This will benefit citizens in providing better treatment options for diseases with unmet medical needs. In addition, this project will provide the state with the benefit of decreased financial burden on the health care system from savings due to more effective treatments. Successful completion of the project will also support the approach of utilizing conventional drug development in regenerative medicine. This will benefit the robust California biotechnology industry by validating this strategy which could lead to additional drugs in this category or in other indications in the future. Finally, this project will benefit the state of California through job creation. Progression of our drug candidate will correlate with increased employment at our company and support contract research organizations.
The goal of this Development Candidate Feasibility Award (DCF) proposal is to establish the feasibility of developing a monoclonal antibody (mAb) or mAb fragment for treatment of inflammatory bowel disorders (IBD), including Crohn’s Disease and ulcerative colitis. The applicant’s group has identified several high affinity mAbs that appear to target a key stem cell pathway involved in normal intestinal homeostasis. By exploiting this activity, the applicant seeks to stimulate the growth and proliferation of intestinal stem cells, thereby enabling regeneration of damaged tissues, even in the context of the hostile, inflammatory environment that characterizes IBD and related disorders. To establish proof of concept and select a lead candidate, a series of five aims has been proposed. First, the applicant will seek reproducible and robust evidence for mAb stimulation of intestinal stem cell proliferation using various in vitro (Aim 1) and in vivo (Aim 2) assessments. Next, the ability of the mAb to support intestinal regeneration in three models of experimental colitis will be determined (Aim 3), as well as the long-term contribution of such treatments to the risk of tumor formation (Aim 4). Finally, the applicant proposes to engineer a protease-resistant version of the lead mAb that could be administered orally (Aim 5). Objective and Milestones - The Target Product Profile (TPP) is scientifically and clinically reasonable but does not specify that the product must not be oncogenic, an issue of critical importance for the proposed patient population. - The objective is appropriate for the DCF award, with milestones designed to establish feasibility of the proposed development candidate for treating IBD. - While some milestones include scientifically and clinically meaningful measures of success, other metrics are vague or lacking in detail, such as those relating to the desired biological activity or the specific properties of the orally available product. Rationale and Significance - The rationale for using the proposed mAbs to modulate a receptor that is known to be overexpressed in bulk cancer and on cancer stem cells is troubling, especially for the proposed patients, who are already predisposed to developing gastrointestinal cancers and have precancerous/cancerous lesions that may be stimulated by such treatment. - It is not clear that stimulation of intestinal stem cell activity by the proposed therapeutic would be sufficient to ameliorate the causes or symptoms of IBD, for which underlying factors such as immune-related chronic inflammation, fibrosis, and intestinal flora may play roles. If the underlying cause is not resolved, the proposed intervention may need to be administered over extended periods, a further safety risk to the vulnerable IBD patient population. - Inflammatory bowel disease, a chronic and potentially debilitating condition that affects over a million Americans, represents an important health problem and unmet medical need. Research Project Feasibility and Design - The preliminary data are only minimally supportive of the proposed research. Evidence for mAb specificity and agonist activity against the designated receptor were not convincing due to a lack of key controls and a paucity of experimental details, such as the nature of the antigen used for mAb derivation, and whether the antibodies recognize their murine counterpart. - The research plan is straightforward but lacking in experimental details. While potential pitfalls are discussed, there is little consideration given to alternative approaches should they become necessary. Moreover, no measures were provided to determine whether project milestones could be reasonably achieved within the three-year timeline. - The plan to evaluate tumorigenicity (Milestone 4) in the colitis model is risky and inefficient. Given the propensity of the targeted patient population to develop cancers, reviewers suggested a more expedient and appropriate safety assessment could be achieved by further testing 1) whether the mAbs stimulate colon/gastric cancer cell lines in culture; and 2) whether they facilitate polyps or pre-existing tumors in xenograft or other mouse models. - The proposed use of three independent IBD models to test mAb activity is well considered, but results would be more meaningful if plans were included to systematically evaluate the effects of mAbs on normal stem cells and ensure that mAb are actually reaching the diseased tissues in all in vivo functional assessments. - The timeline allocated to engineering the mAb for oral availability appears unrealistic. As the engineered structure might give different results than the standard antibody, a reviewer suggested it might be prudent to first test/validate the full mAb in vitro, and then proceed with the engineering plans. Full efficacy testing in the three models could then be undertaken using the oral drug candidate. - Use of the appropriate antibody isotype should be accounted for and integrated into the research plan to avoid potential tissue damage from antibody-dependent cell–mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - The PI, who has expertise in protein chemistry, cell biology and drug discovery, is qualified to oversee this project. While relatively early in his/her career, he/she is the founder of the applicant institution and has engaged an excellent panel of advisors. - The primary members of the research team appear qualified to conduct the proposed studies. Inclusion of an expert in cancer stem cell biology would strengthen the team. - The budget appears heavily allocated towards personnel, whose efforts might be adjusted to reduce overall costs. Collaborations, Assets, Resources and Environment - The project benefits substantially from the presence of two key collaborators, including a world authority on intestinal stem cell biology and discoverer of the receptor targeted by the proposed therapeutic. - No obvious plan for communication between collaborators is described, and no letters of support were provided. - The applicant institution is well situated and adequately resourced. Responsiveness to the RFA - The proposed research adequately and appropriately addresses the objectives of the RFA. - The proposed intervention is not currently represented in CIRM’s translational portfolio.