RAMIHM generates fully human monoclonal antibodies by rapid mRNA immunization of humanized mice and BCR-seq

As a clinical vaccine, lipid nanoparticle (LNP) mRNA has demonstrated potent and broad antibody re-sponses, leading to speculation about its potential for antibody discovery. Here, we developed RAMIHM, a highly efficient strategy for developing fully human monoclonal antibodies that employs rapid mRNA immu-nization of humanized mice followed by single B cell sequencing (scBCR-seq). We immunized humanized transgenic mice with RAMIHM and generated 15 top-ranked clones from peripheral blood, plasma B, and memory B cell populations, demonstrating a high rate of antigen-specificity (93.3%). Two Omicron-specific neutralizing antibodies with high potency and one broad-spectrum neutralizing antibody were discovered. Furthermore, we extended the application of RAMIHM to cancer immunotherapy targets, including a single transmembrane protein CD22 and a multi-transmembrane G protein-coupled receptor target, GPRC5D, which is difficult for traditional protein immunization methods. RAMIHM-scBCR-seq is a broadly applicable platform for the rapid and efficient development of fully human monoclonal antibodies against an assortment of targets.

Automated summary

As a clinical vaccine, lipid nanoparticle (LNP) mRNA has shown strong antibody responses and potential for antibody discovery. A strategy called RAMIHM, which combines rapid mRNA immunization of humanized mice with single B cell sequencing (scBCR-seq), was developed to efficiently generate fully human monoclonal antibodies. RAMIHM was used to immunize humanized transgenic mice and successfully generated highly specific antibodies against antigens. This strategy was also extended to cancer immunotherapy targets, demonstrating its broad applicability in antibody development.