RESEARCH & DEVELOPMENT

Grants and Contracts update

NIAID Adjuvant Development Contract: Development of TRAC-478: A Synthetic Dual TLR Adjuvant Combination System; 9/30/2020 – 9/29/2023

NIAID Adjuvant Development Contract: Boston Children’s Hospital; 9/30/2020 – 9/29/2023

SBIR Phase I Adjuvant Discovery Contract: New small molecule TLR4 agonists for the treatment of Allergic Rhinitis; 8/2018 – 8/2020

R01 Grant Subaward: Immunization against filamentous bacteriophages to prevent bacterial infection; 6/8/2018 – 2/31/2023

SBIR Phase II – Upper Respiratory Tract Infections; 9/1/2019 – 08/31/2121

3 Adjuvant Discovery Sub-Contracts (UM/Duke University, Oregon Health Sciences University, Boston Children’s Hospital); 9/30/2019 – 9/29/2024

Dept. of Defense MRMC Grant for Berkeleylactone development (joint with UM); 2020-2022

Opioid Vaccine Contracts: University of Montana & Boston Children’s Hospital (Subawards to Inimmune); June 2020-May 2022

SBIR Phase II Contract for multi component adjuvant formulations; September 2020-August 2025

Technology

Inimmune technology focuses on the discovery, optimization, and development of new immunomodulatory therapeutics for the treatment or prevention of allergy, autoimmunity, upper respiratory tract infections, and cancer, by targeting innate immune receptors.

Allergy
little girl sneezing
Antibiotics
antibiotics
Autoimmunity
URT Infections
Cancer

Allergy

Allergic rhinitis (AR) affects ≥500 million people worldwide and carries a significant health and economic burden. AR is an inflammatory, IgE-mediated disease characterized by the inflammation of the mucosal lining of the nose that occurs when a person inhales airborne allergens to which he/she is sensitized. The resulting immune reaction leads to the characteristic AR-associated clinical symptoms of nasal congestion, runny nose, sneezing, nasal itching and/or post-nasal drip. Whereas seasonal AR is primarily related to a wide variety of grass, tree and weed pollen allergens, perennial AR is associated with dust mite, mold spore and animal dander allergens.

AR is a prevalent chronic illness in the US, affecting 40 to 60 million individuals, and is the leading chronic medical condition in children. Overall, the estimated direct medical cost of treating AR in the US in 2005 was $11.2 billion and rising-6 The prevalence of AR has increased over the last several decades and this trend is expected to continue because of environmental influences.

A recent study modeling the impact of climate change in Europe estimated that ragweed pollen allergy will become a common health problem across Europe, expanding into areas where it is currently uncommon. Sensitization to ragweed is likely to more than double in Europe, from 33 to 77 million people, by 2041–2060.

AR is frequently associated with multiple comorbid conditions, including asthma, sinusitis, allergic conjunctivitis, otitis media, nasal polyps, and dental malocclusion and can significantly impair quality of life. 19–38% of individuals with AR have concomitant asthma and 80% of asthmatics have concomitant AR.

Evidence also suggests an association between AR and mood disorders such as depression and suicidal behavior. In a number of surveys, up to 74% of adults and adolescents experienced a negative impact on sleep and daily activities because of allergy symptoms, including work and school attendance and performance, and approximately 40–45% of patients with AR report that the discomfort of AR symptoms cannot be ignored or tolerated without drug intervention.

Current therapeutic options are avoidance of allergens, symptomatic medication, and allergen specific immunotherapy (AIT). While avoidance of environmental allergens such as dust mites and pets may reduce rhinitis symptoms, it is challenging and not feasible to consistently avoid outdoor allergens such as pollen and molds.

The most common symptomatic medications used to treat AR include oral and intranasal antihistamines, oral decongestants, intranasal corticosteroids, and oral leukotriene receptor antagonists. Although these pharmacotherapies are effective in treating the symptoms of AR and are generally well tolerated with few side effects, they do not alter the underlying disease and do not prevent disease progression.

AIT is the only treatment modality that has been shown to alter the underlying immunologic mechanisms that cause AR and allergic asthma, with benefits that may last for several years after treatment discontinuation.

AIT improves AR symptoms and the control of comorbid conditions, and can prevent the development of asthma and new allergic sensitivities.

AIT involves the repeated administration of allergens with the aim of reducing symptoms upon subsequent allergen exposure, and inducing long-term tolerance.

AIT is delivered either subcutaneously (SCIT) or sublingually (SLIT) over a period of several years.

One of the major drawbacks of AIT is the potential induction of severe adverse events, especially asthma exacerbation or anaphylaxis with one case of anaphylaxis estimated per 33,300 and 100 million administrations for SCIT and SLIT, respectively.

Other disadvantages of AIT are the long-term commitment needed to complete a full course of treatment (3 to 5 years), resulting in low patient adherence, delayed onset of symptom control (4-8 weeks), and the high costs due to the long duration of treatment.

Additionally, SLIT is FDA approved only for a limited number of allergens (two kinds of grass pollen, one short ragweed and one house dust mite) at this time. An “ultra-short course” SCIT adjuvanted pollen extract vaccine, Pollinex® Quattro is also available in Europe on a “Named Patient” basis. The incorporation of the adjuvant MPL, a Toll-like receptor 4 (TLR-4) agonist, reduces the number of injections from about ninety to four and shortens the treatment duration from three to five years to three weeks, compared to conventional SCIT.

This vaccine has been shown to be clinically effective against seasonal allergies, improve patient compliance, and have persistent long-term effects after three-year treatment. Although systemic reactions are rare and mild, a case of anaphylaxis was reported in 2014.

Additionally, its manufacturing process is not straightforward. Allergen(s) are first extracted, diafiltered, and chemically treated with glutaraldehyde to form allergoids, which are subsequently adsorbed on microcrystalline tyrosine and formulated with MPL. Regulatory approval for this vaccine is being sought in both Europe and North America.

Although pharmacotherapy and AIT are available to relieve symptoms and treat AR, the treatment duration, cost, potential severe side effects and low patient adherence require the development of alternative safe and effective approaches for the treatment of AR. Inimmune is currently developing an intranasal stand-alone TLR4 agonist that would provide relief against AR symptoms within hours of administration. In addition to providing short-term symptom control, this approach also has the potential to deliver long-term disease remission via allergen dependent T-cell and B-cell memory responses.

Unlike AIT, this non allergen-specific approach is expected to provide protection against a wide variety of environmental allergens. Targeting TLR4 to treat AR is based on the potential of TLR agonists to modulate immune responses by reducing the existing allergen-specific Th2 responsiveness and rebalancing it toward a Th1/Treg phenotype.

We anticipate that induction of a Th1/TReg phenotype by TLR4 stimulation will counteract the untoward effects of the Th2 cytokines on the allergic response and re-program the immune response away from allergic hypersensitization. Such global re-programming by a single agent would be especially beneficial for the majority of individuals who are sensitive to multiple allergens and would normally require treatment with multiple vaccines or desensitization therapies.

This approach is expected to accelerate tolerance induction, increase the magnitude of tolerance and decrease the duration of treatment.

This work is partially funded by the following NIAID contract:

  • SBIR Phase I contract: “Discovery of new small molecule TLR4 agonists for the treatment of allergic rhinitis”. 08/2018 – 07/2020 – $634,317

Novel Antibiotics

Microorganisms isolated from extreme environments have proven to be a good source for the discovery of novel, bioactive compounds. A co-culture of two extremophilic fungi, Penicillium fuscum and P. camembertii/clavigerum, that were isolated from a single sample of surface water from the Berkeley Pit Lake superfund site yielded a novel antibiotic, Berkeleylactone A (BA), with activity against methicillin resistant S. aureus (MRSA)It was also screened against sever other gram-positive strains and demonstrated excellent anti-microbial activity. Screening against gram-negative strains demonstrated that the derivitization of the core scaffold results in greatly enhanced gram-negative antibiotic activity without subsequent loss of gram-positive cytotoxicity.

Inimmune possesses an exclusive right to license BA and its derivatives for commercial use and is currently pursuing the development of this unique new class of compounds.

Cancer

Every year, cancer claims the lives of more than half a million Americans and is the second leading cause of death in the United States https://www.cdc.gov/cancer/dcpc/data/types.htm. Novel immunotherapies against both hematological and solid malignancies have come to the forefront of treating these diseases and have demonstrated great promise.

TLR-4 & TLR-7/8 agonists are capable of reducing tumor size and slowing tumor growth in pre-clinical cancer models, especially when used in combination with other approved cancer therapies such as chemotherapy, radiation, and monoclonal antibody therapy.

Using our most potent TLR-4 and 7/8 agonists as a cancer treatments, we are able to significantly reduce tumor size and slow tumor growth in a pre-clinical solid tumor model. When we use these TLR agonists in combination with a monoclonal antibody, these two therapeutics synergize, slowing growth and reducing tumor size significantly more than either alone.

Additionally, in some instances, this combination was able to achieve a cure. We are currently broadening the scope of pre-clinical tumor models and monoclonal antibodies to demonstrate the efficacy of our lead TLR agonists in a wide range of tumor types and to show synergy with FDA approved checkpoint inhibitor monoclonal antibodies.

Upper Respiratory Tract Infections

The insidious and ongoing threat posed by emerging biological pathogens (Ebola, Chikungunya, MERS CoV, SARS, Influenza, Zika), opportunistic infections (Staphylococcus aureus, pneumococcus, Candidiasis, adenovirus) and bioterrorism agents (B. Anthracis, Y. pestis, B. Pseudomallei, F. tularensis, Bunyaviridae, Flaviviridae) are of significant concern to populations around the globe.

Despite recent clinical progress on Zika, MERS and SARS, there are currently no approved vaccines for most of these emerging or opportunistic infections, although several experimental Ebola, Zika and MERS vaccines are undergoing clinical evaluation.

While therapeutic interventions such as antibiotics and antivirals are effective for some pathogens, the increase of antibiotic resistance and antiviral resistance will require a variety of different approaches, including the development of effective vaccines, new antibiotics and anti-viral drugs, to efficiently prevent, neutralize or treat these infections.

Another approach for neutralizing the risk of pathogen exposure is the use of immunomodulators capable of eliciting innate immunity that will non-specifically provide protective resistance against a wide array of biological pathogens. These immunomodulators must be capable of eliciting immunity at mucosal surfaces where the majority of pathogens gain access to the host prior to initiating infection.

Inimmune is developing a safe self-administered intranasal broad-spectrum immunotherapeutic with effective anti-viral activity to prevent upper respiratory tract infections in individuals or populations at risk for emerging or opportunistic pathogen exposure.

The novel therapeutic developed by Inimmune is a synthetic Toll-Like Receptor (TLR) 4 agonist that triggers the host innate immune response within minutes of administration to mediate protection against invading pathogens, including the influenza virus. Because TLR4 activation also initiates a cascade of signals to cells of the adaptive immune arm, this TLR4 agonist can also act as an adjuvant leading to enhanced long-term antigen-specific immunity.

Additionally, the amphipathic nature of this novel agonist is fully compatible with nanoparticle formulations such as liposomes, further improving safety and providing an excellent delivery vehicle for mucosal routes of administration. The new TLR4 agonist developed by Inimmune has the potential to help reduce morbidity and mortality associated with seasonal or pandemic influenza viruses as well as other respiratory pathogens of significant medical concern.

This work is partially funded by the following grants:

  • MBRCT Grant: “Novel Countermeasures for the Prevention of Respiratory Acquired Infections”. 07/2017-06/2018 – $130,108
  • SBIR Phase I Grant: “New synthetic TLR4 agonists”. 02/2018 – 07/2019; $176,805
  • SBIT Phase II Grant: “New synthetic TLR4 agonists”. 09/2019 – 08/2021; $1,017,317

Autoimmunity

An autoimmune disease results from a malfunction in the immune system where healthy cells are mistaken for foreign invaders, causing the immune system to attack these healthy cells.

According to the American Autoimmune Related Diseases Association (AARDA), autoimmune disease affects up to 50 million Americans. Autoimmune diseases include rheumatoid arthritis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), and type I diabetes among many others. Currently, treatment for autoimmune diseases focuses on relieving symptoms because there is no curative therapy.

Inimmune is developing technology that may interrupt the chain of events involved in autoimmune disease by targeting specific receptors involved in the autoimmune disease.

Image adapted from http://healthfactsdirectory.com/autoimmune-disease-what/