While inflammation is part of the normal repair response for healing, when it becomes prolonged and persists, it is damaging and destructive. Several common molecular pathways have been identified that are associated with both aging and low-grade inflammation. Our view is that there are two primary underlying processes that drive inflammaging, or chronic inflammation: Accumulation of senescent cells and activation of inflammasomes. Both of these processes generate pro-inflammatory factors that drive senescence.
Senescent cells remain metabolically active and can influence tissue hemostasis, disease, and aging through their senescence-associated secretory phenotype (“SASP”) factors. Senescence is considered to be a physiologic process and is important in promoting wound healing, tissue homeostasis, regeneration, and regulation of fibrosis. Senescence also plays a role in tumor suppression. The accumulation of senescent cells, due to the aging of our immune cells, drives aging and age-related diseases and conditions. The SASP factors can trigger chronic inflammatory responses and consequently augment chronic inflammatory conditions to promote tumor growth. The connection between senescence and aging was initially based on the observation that senescent cells accumulate in aged tissue. The use of transgenic models has enabled the detection of senescent cells systematically in many age-related disorders. Studies have demonstrated that senescent cells play an adverse role in age-related disorders.
By leveraging our immunology expertise, our Company is developing potentially transformative immunotherapy candidates that use inflammasome modulation and senescent cell clearance to address chronic inflammation linked to age-related diseases. Our approach is to develop immunotherapies that reduce or eliminate the main drivers of chronic inflammation by addressing the underlying development and sustainment of these processes.
HCW9218: Bifunctional Molecule
Our lead molecule, HCW9218, is designed with two functionalities – it rejuvenates the immune system to reduce senescence, and it captures TGF- β to neutralize its immunosuppressive activity. HCW9218 is a novel immunotherapeutic that is a heterodimeric, bifunctional fusion protein complex comprising extracellular domains of the human transforming growth factor-β (“TGF-β”) receptor II, as TGF-β trap for TGF-β neutralization, and a human interleukin (IL)-15/IL-15 receptor α complex for immune-cell stimulation. For further detail, see our publication entitled “Bifunctional TGF-β trap/IL-15 Protein Complex Elicits Potent NK Cell and CD8+ T Cell Immunity against Solid Tumors”, Molecular Therapy 2021 Oct 6;29(10):2949-2962.
HCW9218: Solid Tumors and Therapy-Induced Senescence
Research suggests chemotherapy drugs can trigger what is known as “therapy-induced senescence,” promoting local and systemic inflammation that leads to tumor relapse and metastasis.
Advances in immuno-stimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment. However, novel immunotherapeutics with these dual functions are not frequently constructed. We have used our TOBITM platform to construct a heterodimeric bifunctional fusion molecule, HCW9218, capable of immuno-stimulatory as well as anti-immunosuppressive activity. HCW9218 potently activates NK cells and CD8+ T cells in vitro and in vivo to promote their proliferative and metabolic activities and enhances their cytotoxicity against tumor targets. This fusion complex also exhibited TGF-β neutralizing activity in vitro and sequestered plasma TGF-β in mice and non-human primates.
In addition, preliminary human data readouts from our ongoing Phase1/1b clinical trials to evaluate HCW9218 in solid tumors have provided encouraging data that is consistent with our preclinical findings. For further details, see our published scientific paper entitled “Immunotherapeutic HCW9218 Augments Anti-tumor Activity of Chemotherapy via NK Cell Mediated Reduction of Therapy Induced Senescent Cells,” Molecular Therapy (2022) 30:1171-1187.
HCW9218: Potent Anti-Cancer Treatment
We demonstrated that targeting senescent cells with immunotherapeutics represents an exciting clinical opportunity to maximize the anti-tumor efficacy of chemotherapies and minimize their negative side effects on normal tissues. In combination with therapeutic antibodies and checkpoint blockade therapy, we believe HCW9218 could provide a robust treatment regimen to substantially improve the life span and healthspan of cancer patients. The image below summarizes how HCW9218 has the potential to counter the deficiencies of each of current standard-of-care of anti-cancer therapies.
HCW9218: Expanded Indications
The Company recently published a pivotal scientific paper in Aging Cell entitled, “Immunotherapeutic approach to reduce senescent cells and alleviate senescence-associated secretary phenotype in mice,” with Dr. Hing C. Wong, the Company’s Founder and CEO, as lead and corresponding author. For further details, see Shrestha N. et al., “Immunotherapeutic Approach to Reduce Senescent Cells and Alleviate Senescence-Associated Secretory Phenotype in Mice,” Aging Cell 2023 Mar 26:e13806.
We have demonstrated HCW9218 may have much broader therapeutic potential beyond cancer to other age-related diseases and conditions because of its ability to promote cell-mediated mechanisms to reduce senescent cells and alleviate the proinflammatory factors they secrete, SASP factors, as shown in mice.
The Company has done extensive preclinical research in diabetic db/db and naturally-aged mice. In the diabetic db/db mouse models, subcutaneous administration of HCW9218 reduced senescent islet β cells and SASP resulting in improved gene expression related to glucose tolerance, insulin resistance, and aging index. We also observed the rejuvenation of immune system in naturally-aged mice following HCW9218 treatment. The long-term changes seen in the expression of inflammation and senescence-associated genes in these mice appeared to ‘turn back the clock’. That is, treatment with HCW9218 appears to reverse the expression pattern of key circadian-rhythm genes in naturally-aged mice, as well as genes associated with metabolism and fibrosis in the liver. Long-term studies also showed that HCW9218 treatment improved the physical performance without compromising the healthspan of naturally-aged mice. These data point toward the possibility that we have created a new class of immunotherapeutics for age-related diseases that will fundamentally change the way these diseases are treated.
HCW9302: Treg Expansion
Our lead molecule, HCW9302, is an IL-2-based immunotherapeutic agent, designed to stimulate Treg cells to suppress the activity of inflammasome-bearing cells and inflammatory factors that drives senescence. Treg cells are essential mediators of peripheral tolerance and the global immunoregulatory potential in hosts to self and non-self-antigens. Treg cells achieve this immunoregulatory control through multiple suppressive mechanisms. Alternations in Treg cell development, homeostasis or function can predispose these cells to affect a variety of disease conditions including allergy, autoimmunity, graft rejection, cancer, and response to immunotherapies.
To date, therapeutic approaches to reduce aberrant inflammasome activity have focused on inhibitors of various inflammasome components (i.e., NLRP3 and other NLRs, ASC, Caspase-1) and downstream mediators of inflammation (i.e., IL-1β, IL-18, gasdermin D, etc.) This approach is validated based on the regulatory approval of three biologics that inhibit IL-1β activity (anakinra, a recombinant form of the naturally occurring IL-1Ra; rilonacept, a soluble chimeric Fc fusion protein of IL-1R1 and IL-1R3; and canakinumab, a humanized monoclonal antibody specific for neutralizing IL-1 β ). Together, these molecules are approved for treatment of cryopyrin-associated periodic syndrome, a multisystemic IL-1β–mediated disease due to a gain of function in NLRP3; rheumatoid arthritis; systemic juvenile idiopathic arthritis and other auto-inflammatory diseases. We believe there is considerable interest in other therapeutics that specifically block inflammasome activity upstream of IL-1β. However, these product candidates are still in early phase clinical testing and their bioavailability, off- and on-target toxicity, and utility profiles are still being evaluated.
HCW9302: Autoimmune and Pro-Inflammatory Indications
In the development of HCW9302, our approach has been to deactivate inflammasome pathways in monocytes and macrophages through the immunosuppressive activities of Treg cells induced by our immunomodulator molecules. This approach does not rely on inhibiting specific inflammasome components but rather utilizes natural processes of the immune system to attenuate and rebalance chronic self-perpetuating pro-inflammatory responses. In relevant animal models, we have observed encouraging results using HCW9302 to activate and expand Treg cells for treatment of atherosclerosis and diabetes.
We have conducted extensive preclinical research on HCW9302 for deactivation of inflammasomes to temper the pro-inflammatory environment they create in relevant animal models, including those for atherosclerosis. Our data suggest that HCW9302 functions as a potent agent to stimulate Treg cells that suppress the activity of inflammasome-bearing cells and inflammatory factors. We also observed a long serum half-life compared with rhIL-2 which contribute to the ability of subcutaneously administered HCW9302 to activate and expand Tregs in mice in a well-tolerated dose range without activating proatherogenic CD4+ T cells. This finding also suggests that greater CD25-mediated Treg activation may be superior to “mutein”-based strategies to prevent or diminish IL-2 binding to IL-2Rbg on effector cells. For further details, see our recent publication entitled “A Novel Interleukin-2-Based Fusion Molecule, HCW9302, Differentially Promotes Regulatory T Cell Expansion to Treat Atherosclerosis in Mice,” Frontiers in Immunology 2023 Jan 25;14:1114802.
Using the TOBITM platform, we have successfully developed over 30 molecules that can be administered by subcutaneous injection as well as used in adoptive cell therapy approaches. This modular and tunable technology has allowed us to generate a novel pipeline of internally-developed product candidates capable of activating and targeting desired immune responses and blocking unwanted immunosuppressive activities. We have a library of fusion molecules with cytokines, chemokines, ligands, receptors, and internally-developed single-chain antibodies.