Frontiers in immunology · 2026
Comparative assessment of tissue cross-reactivity and pharmacokinetic half-life of malaria monoclonal antibodies.
СтатьяСравнительное исследованиеНазвание и аннотация: Перевод в очереди
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Fugina William R, Brown Dallas R, Foor Shelby, Ryan Emma C, Cuevas Samuel, Nallar Shreeram, Wolf Dawn, Brown Renita, Deluca Jesse P, Chin Geoffrey C, Raymond Elizabeth J, Raymond James T, Medlin Phil S, Dutta Sheetij
Аннотация
INTRODUCTION: Monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (CSP) are leading clinical candidates for malaria prevention in travelers, military personnel, and pregnant women. Off-target binding and pharmacokinetics (PK) are important considerations during hit-to-lead optimization. As part of a programmatic pivot toward developing malaria mAb candidates, a human tissue cross-reactivity (TCR) and half-life extension (HLE) method optimization was performed using prototype P. falciparum mAbs.
METHODS: TCR assay was performed across 14 human tissue types using the CSP mAbs 317 and 311 and the clinical reference mAb CIS43. The HLE optimization was performed on mAb 311 by introducing Fc modifications that improve affinity for human neonatal Fc receptor (FcRn). Safety and pharmacokinetic parameters of the modified mAb 311-LS and the wild-type 311-WT was determined by intravenous administration in the rhesus PK model at 10 mg/kg dose. Concentration of the mAbs was measured using enzyme-linked immunosorbent assay and biolayer interferometry.
RESULTS: TCR assay showed no membrane binding, but the major repeat-specific mAbs 317 and 311 exhibited varying degrees of positive cross-reactivity to extracellular and cytoplasmic elements in multiple tissue types. In contrast, the clinical reference mAb CIS43 (junctional epitope) showed no TCR positivity. The prototype mAb 311 binding affinity to human neonatal Fc receptor (FcRN) was significantly improved by introducing commonly known HLE mutations. MAb 311-LS was found safe and showed an improved pharmacokinetic profile compared to the wild-type mAb 311.
DISCUSSION: These findings highlight the critical need to evaluate TCR liabilities early in the mAb process development cycle. The successful improvement of mAb 311-LS half-life demonstrates that Rhesus is an excellent model to compare HLE strategies. The developability benchmarks described here will help in the translation of novel, long-acting anti-malarial mAbs.
METHODS: TCR assay was performed across 14 human tissue types using the CSP mAbs 317 and 311 and the clinical reference mAb CIS43. The HLE optimization was performed on mAb 311 by introducing Fc modifications that improve affinity for human neonatal Fc receptor (FcRn). Safety and pharmacokinetic parameters of the modified mAb 311-LS and the wild-type 311-WT was determined by intravenous administration in the rhesus PK model at 10 mg/kg dose. Concentration of the mAbs was measured using enzyme-linked immunosorbent assay and biolayer interferometry.
RESULTS: TCR assay showed no membrane binding, but the major repeat-specific mAbs 317 and 311 exhibited varying degrees of positive cross-reactivity to extracellular and cytoplasmic elements in multiple tissue types. In contrast, the clinical reference mAb CIS43 (junctional epitope) showed no TCR positivity. The prototype mAb 311 binding affinity to human neonatal Fc receptor (FcRN) was significantly improved by introducing commonly known HLE mutations. MAb 311-LS was found safe and showed an improved pharmacokinetic profile compared to the wild-type mAb 311.
DISCUSSION: These findings highlight the critical need to evaluate TCR liabilities early in the mAb process development cycle. The successful improvement of mAb 311-LS half-life demonstrates that Rhesus is an excellent model to compare HLE strategies. The developability benchmarks described here will help in the translation of novel, long-acting anti-malarial mAbs.