In vivo engineered B cells secrete high titers of broadly neutralizing anti-HIV antibodies in mice

Transplantation of B cells engineered ex vivo to secrete broadly neutralizing antibodies (bNAbs) has shown efficacy in disease models. However, clinical translation of this approach would require specialized medical centers, technically demanding protocols and major histocompatibility complex compat...

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Published in:	Nature biotechnology Vol. 40; no. 8; pp. 1241 - 1249
Main Authors:	Nahmad, Alessio D., Lazzarotto, Cicera R., Zelikson, Natalie, Kustin, Talia, Tenuta, Mary, Huang, Deli, Reuveni, Inbal, Nataf, Daniel, Raviv, Yuval, Horovitz-Fried, Miriam, Dotan, Iris, Carmi, Yaron, Rosin-Arbesfeld, Rina, Nemazee, David, Voss, James E., Stern, Adi, Tsai, Shengdar Q., Barzel, Adi
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-08-2022 Nature Publishing Group
Subjects:	631/250/251 631/61/201 Agriculture Animals Antibodies Antibodies, Neutralizing - genetics Autoimmune diseases B-Lymphocytes Biocompatibility Bioinformatics Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Biotechnology Broadly Neutralizing Antibodies Cleavage CRISPR Health care facilities HIV HIV Antibodies - genetics HIV Infections - therapy HIV-1 Human immunodeficiency virus Immunological memory Infectious diseases Life Sciences Lymphocytes B Major histocompatibility complex Memory cells Mice Neutralizing Sequence analysis Staphylococcus aureus Target detection Transplantation
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Summary:	Transplantation of B cells engineered ex vivo to secrete broadly neutralizing antibodies (bNAbs) has shown efficacy in disease models. However, clinical translation of this approach would require specialized medical centers, technically demanding protocols and major histocompatibility complex compatibility of donor cells and recipients. Here we report in vivo B cell engineering using two adeno-associated viral vectors, with one coding for Staphylococcus aureus Cas9 (saCas9) and the other for 3BNC117, an anti-HIV bNAb. After intravenously injecting the vectors into mice, we observe successful editing of B cells leading to memory retention and bNAb secretion at neutralizing titers of up to 6.8 µg ml −1 . We observed minimal clustered regularly interspaced palindromic repeats (CRISPR)–Cas9 off-target cleavage as detected by unbiased CHANGE-sequencing analysis, whereas on-target cleavage in undesired tissues is reduced by expressing saCas9 from a B cell-specific promoter. In vivo B cell engineering to express therapeutic antibodies is a safe, potent and scalable method, which may be applicable not only to infectious diseases but also in the treatment of noncommunicable conditions, such as cancer and autoimmune disease. B cells are engineered in vivo to secrete anti-HIV antibodies
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current affiliation: Tabby Therapeutics LTD. Ness Ziona, Israel. AUTHOR CONTRIBUTIONS A.D.N designed, performed and analyzed the study; C.R.L. performed CHANGE-seq; S.Q.T. supervised CHANGE-seq experiments; N.Z. and T.K. performed bioinformatical analyses; A.S. and R.R.A supervised the bioinformatical analyses; N.Z., M.H.F. and I.R. helped with sample processing; Y.R. helped with vector design and cloning; D.Na. and I.D. designed the B cell progenitor enrichment; M.T. and D.H. performed neutralization assays; D.N. and J.E.V. supervised neutralization assays; I.D. contributed to supervising the study; Y.C. helped with experimental design; A.D.N. and A.B. drafted and revised the manuscript; A.B. Conceptualized and supervised the study.
ISSN:	1087-0156 1546-1696
DOI:	10.1038/s41587-022-01328-9