Building Better Virus Countermeasures — J&J’s BLUE KNIGHT™ Symposium Shows What’s Coming

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With the first wave of vaccines gaining regulatory approval, nascent biotech companies are looking toward the future, exploring new technologies to make vaccines more effective for more people.

For example, some of the companies presenting during Johnson & Johnson’s recent Blue Knight™ Symposium outlined new ways to enhance vaccines for those with quiescent immune systems, innovative strategies to develop more universal vaccines by targeting conserved sites on multiple viruses, and next-generation approaches to target SARS-CoV-2 and other as-yet-unknown pathogen.

The challenge isn’t that existing vaccines are ineffective, but that so little is known about the SARS-CoV-2 virus. Multiple approaches, therefore, are the best backstop to the pandemic.

Unfortunately, vaccines aren’t as effective in senior citizens as they are in their middle-aged counterparts. With that in mind, 7 Hills Pharma is developing an immuno-modulatory countermeasure to enhance vaccine effectiveness in that population.

The lead compound, 7HP349, would be administered orally alongside a pandemic vaccine, said Upendra Marathi, Ph.D., co-founder and CEO of 7 Hills Pharma.

7HP349 works by activating the α4β1and αLβ2 integrins, the cell adhesion molecules that improve immunologic memory and which are vital to producing an immune response. Augmenting cell adhesion also appears to help with T cell activation. In preclinical studies with influenza vaccines, 7HP349 has increased neutralizing antibody titers and seroconversion.

The compound is being developed for coronavirus, influenza and tuberculosis vaccines, without the need for their reformulation, Marathi pointed out. The platform may also extend to other infectious diseases and cancer.

Marathi said he expects the compound to be ready for use with approved vaccines during the second quarter of 2021. “Manufacturing is geared to meet demand in metric ton quantities.”

Autonomous Therapeutics, Inc. is trying to “develop new, effective countermeasures before the next pandemic,” CEO Ariel Weinberger, Ph,D., told the virtual audience.

“The virus of tomorrow won’t look like the virus of today,” he said. “Even in highly related genus there is great diversity. MERS, for example, is 50% different from SARS-CoV-2, especially in the spike proteins.”

Weinberger’s solution to countering evolved or unknown viral pathogens is therapeutic interfering particles (TIPs). These particles use “pan-gene sequences (conserved sites) as the chassis for pan-genus antivirals, and lack the genes needed to replicate in healthy cells,” Weinberger assured.

Against in vitro challenges with H1N1, H3N2, and avian influenza, it showed a four-log reduction in virus titer. Titer reductions also were shown when TIP was administered against the coronaviruses SARS-CoV-2 (a 10-fold reduction), and OC43-CoV (a 100-fold reduction).

Animal studies showed TIPs protected mice against lethal influenza infections, with all the mice not only surviving the 14-day study but doing so with no weight loss.

Autonomous Therapeutics plans to file an investigational new drug application within 12 months and expects to begin Phase Ib/IIa clinical trials within 18 months.

Epic Bio is engineering an antiviral targeting SARS-CoV-2 and RNA viruses that CEO Stanley Lei Qi said “can be developed in weeks rather than months.” The technology, called Pac-Man (prophylactic antiviral CRISPR in human cells), recently transitioned from academic research. It is in the early preclinical phase of development.

In proof-of-concept work, Qi said, “Pac-Man degraded viral RNA by more than 98%.” Analysis showed a group of only six CRISPR-associated RNAs (crRNAs) can target more than 90% of all coronaviruses, Qi and his colleagues at Stanford University reported in Cell 2020 earlier this year.

Unlike traditional vaccines that prime the immune system to recognize and respond to viral proteins or weakened viruses, Pac-Man uses a CRISPR/Cas13 system to recognize and degrade the intracellular viral genome and the viral mRNA. This approach, therefore, targets both the viral genome templates for replication as well as viral gene expression.

The team chose Cas13d because it uses crRNAs, which feature a customizable 22-nucleotide spacer sequence that supports highly specific targeting. It is small, at only 967 amino acids, and offers high specificity and high catalytic activity.

Pac-Man can offer either a complementary or alternative approach to traditional vaccines, Qi said. It is a platform technology that can be used to target multiple viruses and to address any changes to the SARS-CoV-2 virus as it evolves.

These companies and other small, emerging biotechs play a critical role in what J&J called “expanding the shield by igniting early-stage innovation.”

“Of the 800 unique drugs, vaccines, and viral programs for the pandemic, some 70% originated in small, emerging companies,” Michelle McMurry-Heath, M.D., Ph.D., president and CEO of the Biotechnology Innovation Organization (BIO), said during the symposium.

As Blue Knight stressed, these entrepreneurs provide and catalyze the disruptive, innovative, thinking that lays the foundation in our preparedness and response to future threats.

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