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: Immune Checkpoint Inhibitors
Immunotherapy drugs called immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the “off” signal from being sent, allowing the T cells to kill cancer cells. The discovery of immune checkpoint proteins represents a significant breakthrough in the field of cancer immunotherapy.
HCW Biologics’ primary premise is our belief that rejuvenating the immune system creates a systemic change that reduces senescent cells and the proinflammatory factors they secrete. We have seen that HCW9218 can do both in relevant animal models. As we progress in our investigation of the underlying mechanism of action (“MOA”) of HCW9218, we are also gaining a deeper understanding of how this drug works against solid tumors and how it augments anti-tumor activities of immune checkpoint inhibitors (“ICIs”).
The Company has made significant progress in crystalizing our understanding of the anti-cancer MOA of HCW9218, especially in relation to how it complements ICIs. HCW9218 has a unique MOA that we believe allows it to turn a ‘cold’ tumor into a ‘hot’ tumor, potentially opening up the possibility of improving the response rate for checkpoint inhibitors which has remained stubbornly low.
Our excitement about the potential of HCW9218 as a combination therapy with checkpoint inhibitors is fueled by key discoveries made as a result of extensive animal testing in different cold tumor models. First, HCW9218 stimulates and expands progenitor exhausted stem-like T cells and transitory CD8+ effector T cells in the tumor draining lymph nodes followed by trafficking of these cells into the tumors. This opens a pathway for enhancing the anti-tumor activity of checkpoint inhibitors. Secondly, HCW9218 also substantially lowers the TGF-β activity in the tumor microenvironment to lessen immunosuppression. This further boosts the ICI response to block the PD1/PDL1 axis and enhances the anti-tumor activity of HCW9218-activated CD8+ effector T cells.
Rationale of Combining HCW9218 and Immune Checkpoint Inhibitors for Cancer Treatment
For further details, see our published scientific paper entitled Chaturvedi, P. et al., Immunotherapeutic HCW9218 Augments Anti-tumor Activity of Chemotherapy via NK Cell Mediated Reduction of Therapy Induced Senescent Cells, Molecular Therapy, 2022 30:1171-1187; and George, V. et al., Bifunctional immunotherapeutic HCW9218 facilitates recruitment of immune cells from tumor draining lymph nodes to promote antitumor activity and enhance checkpoint blockade efficacy in solid tumors, poster presented at American Association of Cancer Research (2023) 83 (7_Supplement): 4441.
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.
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.
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.