— Tregs Potency, Survival and Engraftment Significantly Enhanced Through Delivery of Engineered Tregs with Tunable IL-2 Signaling Support
CAMBRIDGE, Mass., September 14, 2022 — GentiBio, Inc., a biotherapeutics company developing engineered T regulatory (Treg) cells (EngTregs) therapies for autoimmunity, autoinflammation and allergic diseases, today announced an upcoming presentation of preclinical data relating to the company’s platform technology. The abstract, entitled “Finely Controlled IL-2 Signal in Engineered Human Tregs utilizing a Chemically Induced Signaling Complex (CISC)” will be presented at The Promise of IL-2 Conference in Paris, France on September 16, 2022.
By way of background, Tregs are crucially important in addressing many diseases driven by uncontrolled autologous and allogeneic reactivity. Further, interleukin-2 (IL-2) is the key cytokine for supporting Tregs homeostasis and its functional scarcity underpins many autoimmune diseases. For Tregs therapeutics, IL-2 is essential to support in vivo Tregs stability, proliferation, and persistence, and hence, potency. Tregs do not produce IL-2 themselves which keeps them in a tight control loop with the activated immune effectors which produce it, but in pathologic states, acquired and functional IL-2 scarcity is critically detrimental to Tregs. Various efforts to provide exogenous IL-2 to patients or laboratory animals to boost their Treg functions have shown promise, but systemic delivery of IL-2 also causes activation of other activated immune cell populations and can potentially negatively impact efficacy. Thus, the technology to deliver a finely controlled and robust IL-2 signaling support to tissue-specific Tregs has the greatest potential to restore immune homeostasis and ameliorate disease, GentiBio’s ENFUELTM technology which provides tunable IL-2 signaling to phenotypically stable and antigen specific EngTregs, holds that promise. Following is the information to be presented next week:
- GentiBio’s DURAREGTM platform was used to engineer antigen-specific, FOXP3-stable, human Tregs (EngTregs), and incorporates GentiBio’s ENFUELTM technology, to express a rapamycin-activated, chemically induced signaling complex (CISC), to provide a specific and tunable mechanism to deliver the IL-2 signal to EngTregs.
- In vitro, in the context of appropriate TCR stimulation, these EngTregs were rapidly expanded using subtherapeutic exposures of rapamycin, and in an in vivo mouse model, rapamycin significantly enhanced EngTregs engraftment in an exposure-dependent fashion. In addition, tunable IL-2/CISC mediated stimulation synergized with TCR stimulation to control graded EngTregs population expansion, with highest expansion occurring in the presence of TCR/IL2 stimulation, mirroring the physiologic behavior of endogenous Tregs.
- In vivo, IL-2/CISC mediated stimulation almost tripled the potency of EngTregs (on per dose basis) in a humanized mouse efficacy model.
- In sum, it was demonstrated that a CISC-mediated, IL-2 signaling pathway significantly enhances EngTregs engraftment and potency while avoiding the potential for non-specific activation of potentially pathogenic natural killer (NK) or T effector cells, supporting its investigation for the treatment of autoimmune diseases.
“We are pleased with the continued progress we are making with our platform technology, including the developments detailed in this abstract, which build on a large body of knowledge indicating that deficient Tregs’ access to IL-2 drives many auto- and allo-immune diseases. This recent progress underscores the holistic approach of Genti’s platform to address all key technical hurdles that undermined previous generations of Tregs therapeutics,” stated Adel Nada, M.D., M.S., co-founder and chief executive officer of GentiBio.
“Tregs are the body’s natural defense for keeping our immune systems in balance, so if we can engineer Tregs with all the salient properties to enhance their efficacy and safety, we can achieve potent long-lived drugs that can be potentially applied to many autoimmune, autoinflammatory and allergic diseases,” added Tom Wickham, Ph.D., chief scientific officer of GentiBio.
About GentiBio, Inc.
GentiBio, Inc. is a biotherapeutics company co-founded by pioneers in Treg biology and immunology from Seattle Children’s Research Institute, Benaroya Research Institute, and MIGAL Galilee Research Institute to develop engineered regulatory T cells programmed to treat autoimmune and inflammatory diseases. GentiBio’s Series A financing was led by Matrix Capital Management with participation by Avidity Partners, JDRF T1D Fund, seed investors OrbiMed, RA Capital Management, Novartis Venture Fund, and Seattle Children’s Research Institute. GentiBio’s autologous and allogeneic engineered Tregs platform integrates key technologies designed to successfully (re)establish immune tolerance and overcome major limitations in existing Treg therapeutics. GentiBio is at the forefront of leveraging a unique therapeutic modality that has the potential to address the fundamental cause of many diseases that result from overactivity and/or malfunctioning of the immune system. The company also has a collaboration with Bristol Myers Squibb for the development of Treg therapies for inflammatory bowel diseases. To learn more, visit www.gentibio.com.
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