[R21] Leveraging Large Language Models for the Design of Monoclonal Antibodies Against Malaria
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-03-31
Importo max: 282.757 EUR
Paese: US
Descrizione
Project Summary - Current treatments for Pv are limited, highlighting the need for new therapies targeting
both liver and blood stages.
Relapsing parasites account for up to 80% of infections and disease, establishing
a global reservoir that is difficult to eliminate with current treatments. Blocking liver-stage infections is the most
effective strategy to prevent dormant parasites. A human monoclonal antibody (humAb826827) targets Pv
apical membrane antigen1 (AMA1), blocking both liver and blood stage Pv infections. Large language models
and binder designs will be used to develop novel human monoclonal antibodies targeting Pv invasion ligands,
which will be tested in vitro with Pv clinical isolates. This strategy adapts methods used in enhancing anti-
EGFR mAb, Cetuximab, for cancer therapy. Three approaches will be used to design mAbs: enhancing
existing mAbs, designing new mAbs, and optimizing current mAbs. Enhanced and novel mAbs will be tested
using a collaborative network in Cambodia. The computational approach avoids the bottleneck of isolating
PBMCs from Pv-infected individuals. Developing effective mAb candidates requires optimization across
multiple dimensions, including specific target binding, conformational stability, scalable production, and an
acceptable immunogenicity profile. Aim 1 focuses on improving existing and developing new mAbs based on
826827 and 864865. Computational development of 1000 mAb scaffolds per target epitope will be done using
RFDiffusion, PyRosetta, and MPNN. Optimal mAbs will be selected based on production efficiency,
competition with mAb826827, and blocking capability. Aim 2 focuses on developing new mAbs recognizing
PvCSP VK210 and VK247. Computational approaches from Aim 1 will be applied to PvCSP, using blocking
murine mAbs to guide the generation of new mAbs. Optimal mAbs will be selected based on production
efficiency, competition with murine 2F2, and blocking capability. The project aims to establish which target
proteins are functionally relevant for blocking Pv growth and determine the best therapeutic mAbs, either alone
or in combination.
Istituzione: CASE WESTERN RESERVE UNIVERSITY
PI: Juergen Bosch
Progetto: 1R21AI196274-01
Settori: National Institute of Allergy and Infectious Diseases
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