IMMUNE ACTIVATORS - Enhancing Cell Adhesion to Safely Improve Effectiveness of Vaccines & Cancer Immunotherapies

INTRODUCTION

7 Hills Pharma, of Houston, TX, is focused on the use of pro­prietary, orally available compounds that can activate the im­mune system to enhance the effectiveness of vaccines as well as immuno-oncology therapies for cancer, especially in patient pop­ulations that are most vulnerable to disease.

The company is one of seven start-up companies in the US, Canada, and Europe participating in the Johnson & Johnson (J&J) Innovation – JLABS Blue Knight collaboration with the Biomedical Advanced Research and Development Authority (BARDA) to help battle the COVID-19 pandemic.

BARDA is a component of the Office of the Assistant Secre­tary for Preparedness and Response in the US Department of Health and Human Services. The Blue Knight collaboration is de­signed to identify and accelerate development of innovative ther­apies and diagnostics to address global health security threats. It is anticipated that 7 Hills Pharma and the other six participating companies combined will receive approximately $500k and men­torship from J&J and BARDA.

SARS-CoV-2, the virus that causes COVID-19, first appeared in late 2019 and erupted into a global pandemic infecting more than 100 million people and killing more than 2 million as of the end of January 2021, according to the Johns Hopkins University Coronavirus Resource Center. In the US, 25.8 million people have been infected and more than 430,000 have died.

In response to the urgent need to battle the pandemic, 7 Hills Pharma launched an evaluation of its lead immunostimulant, 7HP349, an oral small-molecule integrin activator, for use with COVID-19 vaccines. 7HP349 already was in development for use with vaccines for influenza.

Both vaccine programs target elderly populations whose im­mune systems have weakened with age. Age-related immune de­ficiencies are the reason 50% of older adults do not respond to protection from influenza vaccinations, and the same will likely occur with COVID-19 vaccinations.

7HP349 activates a class of receptors called integrins that mediate cell-to-cell adhesion, which is necessary for generating immune responses, including those required for vaccine effec­tiveness. This process, however, deteriorates with age. 7HP349 directly activates integrins in an effort to overcome age-related cell adhesion deficiencies. Integrin-mediated cell adhesion is es­sential for any immunotherapy, including immuno-oncology treatments.

7 Hills Pharma launched Phase 1 safety trials of 7HP349 in October 2020. Phase 2 trials of the immunostimulant with COVID-19 and influenza vaccines and immuno-oncology drugs are expected to begin in 2021.

7HP349 HARNESSES THE POWER OF IMMUNOTHERAPY

The immune system is made up of several cell types, such as lymphocytes, neutrophils, and macrophages, which work together to protect the body from infectious diseases and cancer.

Upon recognition of a foreign agent or malignancy in the body, these immune cells are pivotal for generating a cascade of protective defenses to clear the body of the unwanted invaders. The immune system orchestrates this response with integrin-mediated cell adhesion between cells that present the immune system with antigen signatures derived from the infectious agent or malignancy and defending cells that communicate, coordinate, and mi­grate toward the site of the infectious agent or malignancy to fight and eliminate it.

Whether using immunotherapies to target infectious agents or cancerous tu­mors, enabling cell adhesion is essential to harness and direct the power of a strong immune response to the diseases (Figure 1). As immune system cells age, they be­come less capable of mounting responses over time.

7 Hills Pharma’s investigational new drug (IND) application for 7HP349 has been activated by the US FDA. A Phase 1 randomized, placebo-controlled clinical trial to evaluate the safety, tolerability, and pharmacokinetics of 7HP349 was initiated in October 2020. Phase 2 clinical trials with vaccines for COVID-19 and in­fluenza, as well as with immune check­point inhibitors for the treatment of melanoma and other solid tumor cancers are expected in 2021.

INCREASING VACCINE ANTIBODY PRODUCTION TO PROTECT THE MOST SUSCEPTIBLE POPULATIONS

7 Hills Pharma has in-licensed a li­brary of more than 600 first-in-concept, small molecules developed by the Texas Heart Institute that activate integrins α4β1 and αLβ2, which are essential for cell ad­hesion. These receptors are critical for stimulating both humoral and cellular im­munity and can be targeted to strengthen the antigen-specific immune responses of any immunotherapy.

7HP349 and its related compounds are the only immunostimulants of both α4β1 and αLβ2, generating the potential for significantly better immunity. These in­tegrins have been clinically established as therapeutic targets for inhibition to treat in­flammatory diseases and autoimmune dis­orders, but 7 Hills Pharma is the first to activate these same integrins for enhanc­ing immune responses.

Although kick-starting immune re­sponses may suggest risks of harmful overstimulation, the company’s robust preclinical research has established a pos­itive safety profile for 7HP349. 7 Hills Pharma studied the effects of its immunostimulant in autoimmune mouse models. Addition of 7HP349 at concentrations much higher than therapeutic doses did not exacerbate autoimmune side effects.

7HP349 is an allosteric activator that binds directly to α4β1 and αLβ2 on im­mune cells, such as B cells (Figure 2) and T cells (Figure 3), to strengthen and pro­long adhesion to the endogenous ligands, VCAM-1 and ICAM-1, on antigen presenting cells. These specific cell-to-cell interac­tions are responsible for generating antibody production, T cell activation, and T cell memory, all of which are critical re­quirements for a vaccine to be effective against infectious diseases.

In preclinical studies, 7HP349 has demonstrated effectiveness in augmenting vaccine responses against multiple infec­tious agents, including a protein subunit vaccine for SARS-CoV-2, an inactivated virus vaccine for influenza, a DNA vaccine for Trypanosoma cruzi (Chagas disease), and a live attenuated vaccine for My­cobacterium tuberculosis (Tuberculosis).

7 Hills Pharma is the first to conceive of using integrin activators to improve vaccines. There are no direct competitors. Al­though some vaccines are strong enough to elicit an immune response on their own, most are used with admixed vaccine adju­vants or immune stimulants. The unique mechanism of action of the company’s proprietary compounds suggests broad applicability to any existing vaccine and the fact that such compounds are dosed systemically, independent of the vaccine, means there would be no need to refor­mulate existing vaccine stockpiles.

Preclinical studies suggest 7HP349 can be used as an immunostimulant for any vaccine with the potential not only to augment its effectiveness, but also accelerate immune system response, allow for dose sparing, and reduce or eliminate the need for boosters.

The compound has demonstrated the potential to be the first systemic drug used to improve vaccine effectiveness without any change in standard of care for admin­istering the vaccines. By reducing or elim­inating the need for booster shots, 7HP349 also could address concerns about a global shortage of COVID-19 vaccines that require each person to re­ceive two doses.

BREAKING DOWN RESISTANCE TO IMMUNO-ONCOLOGY DRUGS

The major challenge posed by cancer always has been its ability to evade detection by the body’s immune system, leaving patients without a primary defense against the disease. Immuno-oncology drugs are designed to unmask the malignant cells and expose them to attack by the immune system’s killer T cells.

Immuno-oncology drugs such as PD-1 checkpoint inhibitors have become the frontline standard of care for advanced melanoma and other solid tumors. But the treatment’s lack of widespread effective­ness is caused by primary and adaptive re­sistance, resulting in ineffective migration of killer T cells to the site of tumors.

One of the most important predictors of cancer-related mortality for numerous solid tumor cancers is the failure of im­mune cells to access the tumor. In preclinical research, 7HP349 reversed resistance to checkpoint inhibitors in resistant mouse tumor models. These preclinical studies demonstrate that 7HP349 augments the effectiveness of immune checkpoint inhibitors and im­munogenic doses of local ionizing radia­tion.

7HP349 not only enhances trafficking of the T cells into tumors, but also may improve the immune response to tumor anti­gens resulting in enhanced T cell activation similar to the immune response to foreign antigens generated by vaccinations.

If successful, 7HP349 has the poten­tial to change the standard of care treat­ment for solid tumor cancers targeted not only by checkpoint inhibitors, but also by other forms of immuno-oncology thera­pies such as CAR-T cell therapy.

PIONEERING PATENT ESTATE

Due to the novel biology of this class of compounds, 7 Hills Pharma has re­ceived broad patent protection from the US Patent and Trademark Office (USPTO) on four patents covering the use of the company’s integrin activators with any therapeutic antibody, any checkpoint in­hibitor for immuno-oncology, and any vaccine.

The technology was co-invented by scientists at 7 Hills Pharma and the Texas Heart Institute. The company’s four patents are:

• 10,342,866, which covers the composition claims of any integrin acti­vator and any therapeutic antibody.
• 10,709,781, which covers compo­sition claims of any integrin activator and any immune checkpoint inhibitor.
• 10,709,780 and 10,716,849, which cover the composition claims of any vaccine, including one of the com­pany’s novel integrin activators, and an antigen and method claims for admin­istering the vaccine compositions, respectively.

The issuance of these patents indi­cates that the USPTO recognizes the fundamental role of integrins and the unique functionality of the company’s integrin ac­tivators in allowing such broad claims. The patent coverage may enable 7 Hills Pharma to become an essential partner for immuno-oncology and vaccine develop­ers.

In addition, the company is develop­ing 7HP349 for improving umbilical cord blood (UCB) transplants with a $1.9 mil­lion Phase 2 STTR (R42) grant from the National Heart, Lung, and Blood Institute of the US National Institutes of Health (NIH).

The UCB program is aimed at mak­ing cord blood transplants a more viable alternative to bone marrow and peripheral blood as a source of stem cells for trans­plant in treatment of blood cancers and genetic diseases. The major advantage to the use of cord blood cells is that a close donor-patient match is not required. The problem, however, is that it contains fewer stem cells than bone marrow and periph­eral blood, which means it takes longer to reconstitute patients’ immune systems, leaving them vulnerable to infections. In preclinical studies, 7HP349 has demon­strated it can overcome this shortcoming by reducing the time of immune system re­constitution.

SUMMARY

Integrin-mediated cell adhesion is es­sential for establishing the immune sys­tem’s cell-to-cell interactions necessary to mount the body’s natural defenses against infectious diseases and cancer.

The immune system has the potential to independently respond to insults, but in most cases, help is required. Vaccines are designed to train the immune system to recognize specific infectious agents. Simi­larly, immuno-oncology drugs unmask cancers that evade the immune system.

Despite the availability of such im­munotherapies, a large number of people do not respond to treatment, primarily due to a weakened or resistant immune re­sponse. 7 Hills Pharma is developing oral small molecule compounds, administered separately and systemically, to give im­munotherapies the necessary assistance to improve effectiveness for more people.

The company’s integrin activators are the first of their kind to be deployed as immunostimulants for vaccines against COVID-19 and influenza and for immune checkpoint inhibitors against malignant melanoma and other solid tumor cancers.

7 Hills Pharma received a 2-year, $2-million Small Business Innovation Re­search (SBIR) grant from the US National Institutes of Health to support Phase 1 safety trials of 7HP349. Phase 2 trials of the immunostimulant to augment the effectiveness of COVID-19 and influenza vaccines, as well as checkpoint inhibitors, are expected to begin in 2021.

The company is seeking partners to pursue all three indications (aPD-1 resist­ant tumors, geriatric seasonal influenza, and geriatric COVID-19) to establish 7HP349 proof-of-concept as a safe, sys­temic immune activator and seek partnerships with vaccine and immuno-oncology producers for what could be a game-changer for immunotherapies.

To view this issue and all back issues online, please visit www.drug-dev.com.

Dr. Siddhartha De is a pharmacologist by training and is the Senior Director of Development at 7 Hills Pharma, where he has been deeply involved with the preclinical development of 7HP349 and its preparation for clinical readiness. He earned his PhD in Biochemistry in 2001 from the University of Mississippi School of Medicine, during which he elucidated the role of different H1 histone variants in the architecture of chromatin in the cell nucleus, and the functional consequence of this chromatin organization on nuclear processes, such as transcription, replication, and recombination. After his PhD, he worked at the University of Virginia for his post-doctoral research work, where he focused on the role of estrogen and androgen receptors in cancer, and at Luna Innovations to kick-start different Department of Defense (DoD)-funded programs to address homeland defense and counter bioterrorism. For the next several years, he worked for the drug discovery and development operations at Eurofins Advinus, where he headed in vitro Discovery Biology and the CNS therapeutic area, and led several programs to clinical candidacy. Additionally, he has worked in Project Management and Business Development, representing outlicensing strategy, partnerships, and contract services.

Dr. Peter Vanderslice is the Director, Biology of the Molecular Cardiology Research Laboratory at the Texas Heart Institute in Houston, TX, and is a 7 Hills Pharma Co-founder, investor, and an inventor of the company’s technology. He has spent over 25 years leading teams focused on the development of small molecule compounds that bind and modulate the function of integrins, selectins, and chemokine receptors. He has authored numerous peer-reviewed publications, reviews, and book chapters focusing on the biological function and therapeutic targeting of cell adhesion molecules. Much of his professional career has been in the pharmaceutical industry, where he gained extensive experience with each stage of the pipeline from discovery to progression into clinical trials. As Senior Director of Drug Discovery at Encysive Pharmaceuticals, he led teams developing therapeutics for autoimmune and inflammatory diseases. Three such programs resulted in compounds entering clinical trials. He joined the Texas Heart Institute in 2008 and has continued to discover and characterize integrin-targeted small molecules as potential therapeutics. These include a family of integrin activators, licensed to 7 Hills Pharma, that function as immune stimulants. He earned his PhD in Biochemistry from the University of Texas at Austin and trained as a Parker B. Francis post-doctoral fellow in the Cardiovascular Research Institute at the University of California, San Francisco.