Moldovan Loomis, C. | bioRxiv Science

bioRxiv2023

AI-based antibody discovery platform identifies novel, diverse and pharmacologically active therapeutic antibodies against multiple SARS-CoV-2 strains

A critical aspect of a successful pandemic response is expedient antibody discovery, manufacturing and deployment of effective lifesaving treatments to patients around the world. However, typical drug discovery and development is a lengthy multi-step process that must align drug efficacy with multiple developability criteria and can take years to complete. In this context, artificial intelligence (AI), and especially machine learning (ML), have great potential to accelerate and improve the optimization of therapeutics, increasing their activity and safety as well as decreasing their development time and manufacturing costs. Here we present a novel, cost-effective and accelerated approach to therapeutic antibody discovery, that couples AI-designed human antibody libraries, biased for improved developability attributes with high throughput and sensitive screening technologies. The applicability of our platform for effective therapeutic antibody discovery is demonstrated here with the identification of a panel of human monoclonal antibodies that are novel, diverse and pharmacologically active. These first-generation antibodies, without the need for affinity maturation, bind to the SARS-CoV-2 spike protein with therapeutically-relevant specificity and affinity and display neutralization of SARS-CoV-2 viral infectivity across multiple strains. Altogether, this platform is well suited for rapid response to infectious threats, such as pandemic response. IMPORTANCEExpedient discovery and manufacturing of lifesaving therapeutics is critical for pandemic response. The recent COVID pandemic has highlighted the current inefficiencies and the need for improvements. To this end, we present our therapeutic antibody discovery platform that couples artificial intelligence (AI) and innovative high throughput technologies, and we demonstrate its applicability to rapid response. This platform enabled the isolation, characterization, and rapid identification of effective broadly neutralizing SARS-CoV-2 antibodies with good developability attributes, anticipated to fit our current process development and manufacturing platform. As such, this would benefit cost-of-goods and improve therapeutic access to patients. The AI-derived antibodies represent an advantageous therapeutic modality that can be developed and deployed fast, thus well suited for rapid response to infectious threats, such as pandemic response.

immunology↗

bioRxiv2020

PACAP induces light aversion in mice by an inheritable mechanism independent of CGRP

The neuropeptides CGRP and PACAP have emerged as mediators of migraine, yet the potential overlap of their mechanisms remains unknown. Infusion of PACAP, like CGRP, can cause migraine in people, and both peptides share similar vasodilatory and nociceptive functions. In this study, we have used light aversion in mice as a surrogate for migraine-like photophobia to compare CGRP and PACAP and ask whether CGRP or PACAP actions were dependent on each other. Similar to CGRP, PACAP induced light aversion in outbred CD-1 mice. The light aversion was accompanied by increased resting in the dark, but not anxiety in a light-independent open field assay. Unexpectedly, about a third of the CD-1 mice did not respond to PACAP, which was not seen with CGRP. The responder and nonresponder phenotypes were stable, inheritable, and not sex-linked, although there was generally a trend for greater responses among male mice. RNA-seq analysis of trigeminal ganglia yielded hieriechial clustering of responder and nonresponder mice and revealed a number of candidate genes, including greater expression of pituitary hormones and receptors in a subset of responder mice. Importantly, an anti-PACAP monoclonal antibody could block PACAP-induced light aversion but not CGRP-induced light aversion. Conversely, an anti-CGRP antibody could not block PACAP-induced light aversion. Thus, we propose that CGRP and PACAP act by independent convergent pathways that cause a migraine-like symptom in mice. SignificanceThe relationship between the neuropeptides CGRP and PACAP in migraine is relevant given that both peptides can induce migraine in people, yet to date only drugs that target CGRP are available. Using an outbred strain of mice, we were able to show that most, but not all, mice respond to PACAP in a preclinical photophobia assay. Our finding that CGRP and PACAP monoclonal antibodies do not cross-inhibit the other peptide indicates that CGRP and PACAP actions are independent and suggests that PACAP-targeted drugs may be effective in patients who do not respond to CGRP-based therapeutics.

neuroscience↗