Biology subjects

Walsh, S. R.

Publications and source records attributed to Walsh, S. R..

3 recordsLinked to original sources

bioRxiv2026

Antibody-recruiting molecules based on mimotope fusion peptides and a dimeric antibiotic

New therapeutic approaches are needed to treat infections due to multidrug resistant (MDR) Gram-negative bacteria. The use of antibody-recruiting molecules (ARMs) is a promising approach to address the MDR problem given their potential to engage both the adaptive and innate immune systems to treat bacterial infections. Here we present two new strategies to create ARMs. First, we show that a 9-mer antimicrobial peptide (K6) can be fused to a 11-mer mimotope peptide recognized by antibodies targeting the Vibrio cholerae O1 O-antigen to produce an ARM peptide (FZ5) that can render E. coli more sensitive to complement killing in the presence of antibodies that recognize this mimotope. FZ5 can drive killing by complement in the presence of rabbit antibodies raised against O1 serogroup V. cholerae as well as antibodies present in human sera elicited by immunization with the live attenuated cholera vaccine PanChol. We also describe a strategy that combines bacterial surface binding with hapten display through the use of homodimers of the antibiotic streptomycin (Str) and anti-Str antibodies elicited by Str-protein conjugate vaccines. When combined with dimeric Str derivatives and human complement, polyclonal anti-streptomycin antisera kills E. coli by targeting the Str hapten. Dimeric forms of Str also significantly enhanced killing of a Str-resistant P. aeruginosa clinical isolate dependent on low levels of human complement and polyclonal anti-Str antibody. Together these data suggest that anti-bacterial ARM molecules based on mimotope display through simple synthetic fusion peptides, or dimeric haptens have promise as new approaches for the treatment of MDR bacterial infections.

microbiology↗

bioRxiv2025

Effects and mechanisms of monoclonal and polyclonal human antibodies in protection of humanized mice from HIV-1 challenge

Recent clinical trials of both active and passive immunization demonstrate the barriers to the successful development of efficacious preventative HIV-1 vaccines and prophylactic antibody treatments. More facile means to explore these interventions in preclinical models could fill key gaps in knowledge and contribute to identifying and optimizing the most promising interventions. Here we report simple adaptations to standard virus challenge strategies in the humanized mouse model that support evaluation of antibody-mediated protection from infection with fewer high stakes design choices and demonstrate evaluation of protection afforded by polyclonal human serum IgG antibodies (pAbs) and monoclonal antibodies (mAbs) with variable pharmacokinetic (PK) and functional profiles. Using these adaptations, we observed that both neutralization and Fc-mediated effector functions contribute to the in vivo antiviral activity of broadly-neutralizing antibody VRC01, that confounding of results due to differences in mAb PK can be overcome, and most promisingly, that polyclonal human serum IgG that exhibits potent neutralizing and Fc-effector function can protect from infection. Collectively, this work demonstrates insights into antibody-mediated protection and methods that hold promise in supporting testing the protection from HIV-1 afforded by human pAb responses induced by vaccination.

immunology↗

bioRxiv2024

Boosting of CAR-T cells with rhabdovirus is limited by type I interferon and rapid contraction

Rhabdovirus vaccines that encode tumour-associated antigens are potent boosting agents for adoptively transferred tumour-specific T cells. Employing rhabdovirus vaccines to boost adoptively transferred T cells relies on a priori knowledge of tumour epitopes, isolation of matched epitope-specific T cells, and a personalized vaccine, which limit clinical feasibility. Here, we investigated a universal strategy for boosting transferred tumour-specific T cells where boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vesicular stomatitis virus (VSV) vaccine encoding the CAR-target. Boosting CAR-engineered tumour-specific T cells with paired VSV vaccines was associated with robust T cell expansion and delayed tumour progression in syngeneic models. CAR-T cell expansion and anti-tumour function was enhanced by blocking IFNAR1. However, vaccine-boosted CAR-T cells rapidly contracted and antigen-positive tumours re-emerged. In contrast, when the same T cells were boosted with VSV encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumour-specific endogenous cells expanded in parallel, and tumour cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumour-reactive T cells to achieve long-term tumour control.

immunology↗