Generative artificial intelligence (AI) has the potential to greatly increase the speed, quality and controllability of antibody design. Traditional de novo antibody discovery requires time and resource intensive screening of large immune or synthetic libraries. These methods also offer little control over the output sequences, which can result in lead candidates with sub-optimal binding and poor developability attributes. Several groups have introduced models for generative antibody design with promising in silico evidence, however, no such method has demonstrated de novo antibody design with experimental validation. Here we use generative deep learning models to de novo design antibodies against three distinct targets, in a zero-shot fashion, where all designs are the result of a single round of model generations with no follow-up optimization. In particular, we screen over 400,000 antibody variants designed for binding to human epidermal growth factor receptor 2 (HER2) using our high-throughput wet lab capabilities. From these screens, we further characterize 421 binders using surface plasmon resonance (SPR), finding three that bind tighter than the therapeutic antibody trastuzumab. The binders are highly diverse, have low sequence identity to known antibodies, and adopt variable structural conformations. Additionally, these binders score highly on our previously introduced Naturalness metric, indicating they are likely to possess desirable developability profiles and low immunogenicity. We open source the HER2 binders and report the measured binding affinities. These results unlock a path to accelerated drug creation for novel therapeutic targets using generative AI combined with high-throughput experimentation.

Tuberculosis (TB) is the leading cause of death in humans by a single infectious agent worldwide with approximately two billion humans latently infected with the bacterium Mycobacterium tuberculosis. Currently, the accepted method for controlling the disease is Tuberculosis Directly Observed Treatment Shortcourse (TB‐DOTS). This program is not preventative and individuals may transmit disease before diagnosis, thus better understanding of disease transmission is essential. Using whole‐genome sequencing and single nucleotide polymorphism analysis, we analyzed genomes of 145 M. tuberculosis clinical isolates from active TB cases from the Rubaga Division of Kampala, Uganda. We established that these isolates grouped into M. tuberculosis complex (MTBC) lineages 1, 2, 3, and 4, with the most isolates grouping into lineage 4. Possible transmission pairs containing ≤12 SNPs were identified in lineages 1, 3, and 4 with the prevailing transmission in lineages 3 and 4. Furthermore, investigating DNA codon changes as a result of specific SNPs in prominent virulence genes including plcA and plcB could indicate potentially important modifications in protein function. Incorporating this analysis with corresponding epidemiological data may provide a blueprint for the integration of public health interventions to decrease TB transmission in a region.

Infections caused by Streptococcus pneumoniae (pneumococcus, Spn) manifest in several forms such as pneumonia, meningitis, sinusitis or otitis media and are associated with severe morbidity and mortality worldwide. While current vaccines and antibiotics are available to treat Spn infections, the rise of antibiotic resistance and limitations of the vaccines to only certain Spn serotypes urge the development of novel treatments against Spn. Hypothiocyanite (OSCN-) is a natural antimicrobial product produced by the body’s own innate immune system to fight a variety of pathogens. We recently showed that OSCN- is also capable of killing Spn in vitro. OSCN- is an oxidative agent attacking microbes in a nonspecific manner, is safe for the host and also has anti-inflammatory effects that make it an ideal candidate to treat a variety of infections in humans. However, OSCN- has a short life span that makes its use, dosage and administration more problematic. This minireview discusses the antimicrobial mechanism of action of OSCN- against Spn and elaborates on the potential therapeutic use of OSCN- against Spn and other infectious agents, either alone or in combination with other therapeutic approaches.