By leveraging our immunology expertise, HCW is developing potentially transformative immunotherapy candidates that use inflammasome modulation and senescent cell clearance to address chronic inflammation linked to age-related diseases.
Advances in immuno-stimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment. Our lead product candidate, HCW9218, is an innovative cancer immunotherapeutic designed to do both.
Our gateway indication is oncology. We believe HCW9218 can stimulate anti-tumor effector immune cell responses, block transforming growth factor-β (“TGF-β”) immunosuppressive activity, eliminate chemotherapy-induced senescent cells in tumors and normal tissues (i.e., senolytic effect), and reduce senescence-associated secretory phenotype (“SASP”) factor activity (i.e., senomorphic effect).
HCW9218: Bifunctional Molecule
Our lead molecule, HCW9218, is designed with both of these functionalities – it rejuvenates the immune system to reduce senescence, and it captures TGF-ß 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.
The unique combination of a TGF-β receptor, that neutralizes an extremely immunosuppressive cytokine secreted by tumors, with the IL-15, a potent cytokine that stimulates the NK- and CD8+– cell cytotoxicity, results in an immunotherapeutic that has the potential to drive significant bifunctional antitumor action. HCW Biologics has data from preclinical animal studies that demonstrated that monotherapy treatment with HCW9218 was well tolerated, without causing bleeding episodes reported while using antibody-based TGF-β neutralizers at high dose levels.
HCW9218 and Therapy-Induced Senescence
Cellular senescence is believed to play a key role in cancer recurrence and metastasis11,2. The current standard of care for cancer has improved survival rates for many patients, but the risk of recurrence remains high. 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. To attenuate the tumor-promoting effects of therapy-induced senescent cells, we seek to reduce senescent cancer and non-cancerous cells post-chemotherapy, and by doing so, optimize the therapeutic efficacy of chemotherapy and improve disease outcomes.
- Fitsiou E et al., Biological Functions of Therapy-Induced Senescence in Cancer. Sem. in Can. Biol. Mar 26, 2021.
- Cuollo L et al., The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases. Biology 2020, 9, 485.
In experimental animal models using HCW9218 as an adjunct therapy to FDA-approved cancer treatments, we demonstrated that HCW9218, with IL-15 immunostimulatory and TGF-β antagonist activities, can activate and promote proliferations, and metabolic and tumor-targeted cytotoxic activities of NK cells and CD8+ T cells and neutralize TGF-β. HCW9218 treatment resulted in promoting immune-cell infiltration into the tumors, lowering the immunosuppressive tumor microenvironment, and enhancing the cytotoxicity of infiltrated immune cells to eliminate chemotherapy-induced TIS cancer cells. These studies also demonstrated that HCW9218 treatment following DTX chemotherapy further enhanced anti-tumor efficacy of therapeutic antibody TA99 and anti-PDL-1 therapy. We also showed that HCW9218 treatment decreased TIS and lower SASP factors in off-target tissues in tumor-bearing mice caused by chemotherapy. Thus, HCW9218-based treatment has great potentials of eliminating TIS cancer and off-target tissue cells, providing potent immune cell-mediated augmentation of the chemotherapies anti-tumor activities and potentially lessen the side effects of chemotherapies, and enhancing anti-tumor efficacy of therapeutic and checkpoint antibodies.
HCW9218: Potent Anti-Cancer Treatment
The table below summarizes how HCW9218 has the potential to counter the deficiencies of each of current standard-of-care of anti-cancer therapy.
Inflammasomes are expressed in innate immune cells. When these cells are stimulated by various signals, the inflammasomes become active and the cells release inflammatory factors. In certain conditions, these signaling pathways persist leading to chronic inflammatory responses and associated tissue destruction. To date, therapeutic approaches to reduce aberrant inflammasome activity have focused on inhibitors of various inflammasome components and downstream mediators of inflammation.
We believe there is considerable interest in therapeutics that specifically block inflammasome activity upstream. 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 investigated.
Our approach is to deactivate inflammasome pathways in monocytes and macrophages through the immunosuppressive activities of regulatory T cells (“Treg”) with our immunomodulator molecule. This approach does not rely on inhibiting specific inflammasome components but utilizes natural processes of the immune system to attenuate and rebalance chronic self-perpetuating proinflammatory responses.
HCW9302: Treg Expansion
We are developing HCW9302, an IL-2-based immunotherapeutic, to stimulate Treg cells to suppress the activity of inflammasome-bearing cells and inflammatory factors.
To use T cell-based adoptive therapies, including Treg cells, ex-vivo cell stimulation step is required for GMP manufacturing setting. Anti-CD3/anti-CD28 antibody-coated magnetic beads is most commonly used for cell stimulation and expansion in combination with IL-2. If using this approach, methods must be developed to ensure T cells are “bead free” at the culture harvest and prior to infusion into patients. HCW has developed a process that can expand Treg and CAR-Treg cells without using magnetic bead-based stimulation.
HCW has developed a method of employing HCW9302 to effectively substitute IL-2 and anti-CD3/antiCD28-coated magnetic beads, respectively, for Treg cell stimulation and expansion without using rapamycin. We use a soluble fusion protein complex that can be easily removed from the culture with simple wash steps which eliminates the need for bead removal, saving time and processing cost, and enhancing cell recovery. Our processes result in Treg cells with increased the purity, consistency, and the effector functions.
OTHER AGE-ASSOCIATED DISEASES
We believe age-related low-grade chronic inflammation, or “inflammaging,” is a significant contributing factor to several chronic diseases and conditions, such as cancer, cardiovascular disease, diabetes, neurodegenerative disease, and autoimmune disease. We believe our approach has the potential to provide an innovative treatment of these age-related diseases.