Therapeutic Activity of Type 3 Streptococcus pneumoniae Capsule Degrading Enzyme Pn3Pase

Abstract

Purpose Streptococcus pneumoniae (Spn) serotype 3 (Spn3) is considered one of the most virulent serotypes with resistance to conventional vaccine and treatment regimens. Pn3Pase is a glycoside hydrolase that we have previously shown to be highly effective in degrading the capsular polysaccharide of type 3 Spn, sensitizing it to host immune clearance. To begin assessing the value and safety of this enzyme for future clinical studies, we investigated the effects of high doses of Pn3Pase on host cells and immune system. Methods We assessed the enzyme’s catalytic activity following administration in mice, and performed septic infection models to determine if prior administration of the enzyme inhibited repeat treatments of Spn3-challenged mice. We assessed immune populations in mouse tissues following administration of the enzyme, and tested Pn3Pase toxicity on other mammalian cell types in vitro . Results Repeated administration of the enzyme in vivo does not prevent efficacy of the enzyme in promoting bacterial clearance following bacterial challenge, with insignificant antibody response generated against the enzyme. Immune homeostasis is maintained following high-dose treatment with Pn3Pase, and no cytotoxic effects were observed against mammalian cells. Conclusions These data indicate that Pn3Pase has potential as a therapy against Spn3. Further development as a drug product could overcome a great hurdle of pneumococcal infections.

Pneumococcal Surface Proteins as Virulence Factors, Immunogens, and Conserved Vaccine Targets

“…In recent years, studies on molecular mechanisms of glycoconjugate vaccine-induced immune responses have shed light on the knowledge-based vaccine design ( Avci et al., 2011 ; Avci et al., 2012 ; Middleton et al., 2017 ; Sun et al., 2019 ). Researchers have found new therapeutic approaches such as capsule-degrading enzymes ( Middleton et al., 2018a ; Middleton et al., 2018b ; Paschall et al., 2020 ; Wantuch et al., 2021 ), capsule-specific protective antibodies ( Babb et al., 2021 ; Ozdilek et al., 2021 ; Huang et al., 2021 ), or improved conjugation strategies ( Duke et al., 2021 ). However, identifying and testing vaccine candidates employing conserved Spn surface protein immunogens remain an important area of research with the goal of serotype-independent coverage.…”