Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages

• DOI: 10.1073/pnas.2315354120
• Publication Date: 2024-01-09T18:46:43Z
• Authors: Harold Marcotte; Yunlong Cao; Fanglei Zuo; Luca Simonelli; Josè Camilla Samm...; Mattia Pedotti; Rui Sun; Irene Cassaniti; Marie Hagbom; Antonio Piralla; Jinxuan Yang; Likun Du; Elena Percivalle; Federico Bertoglio; Maren Schubert; Hassan Abolhassani; Natalia Sherina; Concetta Guerra; Stephan Borte; Nima Rezaei; Makiko Kumagai-Br...; Yintong Xue; Chen Su; Qihong Yan; Ping He; Caroline Grönwall; Lars Klareskog; Luigi Calzolai; Andrea Cavalli; Qiao Wang; Davide F. Robbiani; Michael Hust; Zhengli Shi; Liqiang Feng; Lennart Svensson; Ling Chen; Linlin Bao; Fausto Baldanti; Junyu Xiao; Chuan Qin; Lennart Hammarström; Xinglou Yang; Luca Varani; Xiaoliang Sunney Xie; Qiang Pan-Hammars...
• Keywords: Avidity; Secretory component; Neonatal Fc receptor

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat the effectiveness vaccines therapeutic antibodies. We have previously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by mRNA is associated with surge in breakthrough infections. Here, we further show intramuscular and/or inactivated cannot sufficiently boost secretory IgA uninfected individuals, particularly against variant. thus engineered characterized recombinant monomeric, dimeric, IgA1 antibodies derived from four neutralizing IgG monoclonal (mAbs 01A05, rmAb23, DXP-604, XG014) targeting receptor-binding domain spike protein. Compared their parental antibodies, dimeric showed higher activity different variants concern (VOCs), part due increased avidity. Importantly, or form DXP-604 antibody significantly outperformed its antibody, neutralized BA.1, BA.2, BA.4/5 25- 75-fold increase potency. In human angiotensin converting enzyme 2 (ACE2) transgenic mice, single intranasal dose conferred prophylactic protection BA.5. Thus, delivered nasal administration may potentially be exploited for treatment prevention infection, thereby providing alternative tool combating immune evasion current circulating and, potentially, future VOCs.