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Article: In vivo

Pan, Andi / Bailey, Charles C / Ou, Tianling / Xu, Jinge / Liu, Xin / Hu, Baodan / Crynen, Gogce / Skamangas, Nickolas / Bronkema, Naomi / Tran, Mai / Mu, Huihui / Zhang, Xia / Yin, Yiming / Alpert, Michael D / He, Wenhui / Farzan, Michael

bioRxiv : the preprint server for biology

2024

Abstract: Many human proteins have been repurposed as biologics for clinical use. These proteins have been engineered ... ...

Abstract	Many human proteins have been repurposed as biologics for clinical use. These proteins have been engineered with
Language	English
Publishing date	2024-02-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.03.578630
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Article: In vivo

Research square

2024

Abstract: Many human proteins have been repurposed as biologics for clinical use. These proteins have been engineered ... ...

Abstract	Many human proteins have been repurposed as biologics for clinical use. These proteins have been engineered with
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3922904/v1
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Article ; Online: In vivo affinity maturation of mouse B cells reprogrammed to express human antibodies.

Yin, Yiming / Guo, Yan / Jiang, Yuxuan / Quinlan, Brian / Peng, Haiyong / Crynen, Gogce / He, Wenhui / Zhang, Lizhou / Ou, Tianling / Bailey, Charles C / Farzan, Michael

Nature biomedical engineering

2024

Abstract: Mice adoptively transferred with mouse B cells edited via CRISPR to express human antibody variable chains could help evaluate candidate vaccines and develop better antibody therapies. However, current editing strategies disrupt the heavy-chain locus, ... ...

Abstract	Mice adoptively transferred with mouse B cells edited via CRISPR to express human antibody variable chains could help evaluate candidate vaccines and develop better antibody therapies. However, current editing strategies disrupt the heavy-chain locus, resulting in inefficient somatic hypermutation without functional affinity maturation. Here we show that these key B-cell functions can be preserved by directly and simultaneously replacing recombined mouse heavy and kappa chains with those of human antibodies, using a single Cas12a-mediated cut at each locus and 5' homology arms complementary to distal V segments. Cells edited in this way to express the human immunodeficiency virus type 1 (HIV-1) broadly neutralizing antibody 10-1074 or VRC26.25-y robustly hypermutated and generated potent neutralizing plasma in vaccinated mice. The 10-1074 variants isolated from the mice neutralized a global panel of HIV-1 isolates more efficiently than wild-type 10-1074 while maintaining its low polyreactivity and long half-life. We also used the approach to improve the potency of anti-SARS-CoV-2 antibodies against recent Omicron strains. In vivo affinity maturation of B cells edited at their native loci may facilitate the development of broad, potent and bioavailable antibodies.
Language	English
Publishing date	2024-03-14
Publishing country	England
Document type	Journal Article
ISSN	2157-846X
ISSN (online)	2157-846X
DOI	10.1038/s41551-024-01179-6
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Article: In vivo

Yin, Yiming / Guo, Yan / Jiang, Yuxuan / Quinlan, Brian / Peng, Haiyong / Crynen, Gogce / He, Wenhui / Zhang, Lizhou / Ou, Tianling / Bailey, Charles C / Farzan, Michael

bioRxiv : the preprint server for biology

2023

Abstract: CRISPR-edited murine B cells engineered to express human antibody variable chains proliferate, class switch, and secrete these antibodies in vaccinated mice. However, current strategies disrupt the heavy-chain locus, resulting in inefficient somatic ... ...

Abstract	CRISPR-edited murine B cells engineered to express human antibody variable chains proliferate, class switch, and secrete these antibodies in vaccinated mice. However, current strategies disrupt the heavy-chain locus, resulting in inefficient somatic hypermutation without functional affinity maturation. Here we show that recombined murine heavy- and kappa-variable genes can be directly and simultaneously overwritten, using Cas12a-mediated cuts at their 3'-most J segments and 5' homology arms complementary to distal V segments. Cells edited in this way to express the HIV-1 broadly neutralizing antibodies 10-1074 or VRC26.25-y robustly hypermutated and generated potent neutralizing plasma in vaccinated recipient mice. 10-1074 variants isolated from these mice bound and neutralized HIV-1 envelope glycoprotein more efficiently than wild-type 10-1074 while maintaining or improving its already low polyreactivity and long
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.20.563154
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Article ; Online: Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2.

Tianling Ou / Huihui Mou / Lizhou Zhang / Amrita Ojha / Hyeryun Choe / Michael Farzan

PLoS Pathogens, Vol 17, Iss 1, p e

2021 Volume 1009212

Abstract: Hydroxychloroquine, used to treat malaria and some autoimmune disorders, potently inhibits viral infection of SARS coronavirus (SARS-CoV-1) and SARS-CoV-2 in cell-culture studies. However, human clinical trials of hydroxychloroquine failed to establish ... ...

Abstract	Hydroxychloroquine, used to treat malaria and some autoimmune disorders, potently inhibits viral infection of SARS coronavirus (SARS-CoV-1) and SARS-CoV-2 in cell-culture studies. However, human clinical trials of hydroxychloroquine failed to establish its usefulness as treatment for COVID-19. This compound is known to interfere with endosomal acidification necessary to the proteolytic activity of cathepsins. Following receptor binding and endocytosis, cathepsin L can cleave the SARS-CoV-1 and SARS-CoV-2 spike (S) proteins, thereby activating membrane fusion for cell entry. The plasma membrane-associated protease TMPRSS2 can similarly cleave these S proteins and activate viral entry at the cell surface. Here we show that the SARS-CoV-2 entry process is more dependent than that of SARS-CoV-1 on TMPRSS2 expression. This difference can be reversed when the furin-cleavage site of the SARS-CoV-2 S protein is ablated or when it is introduced into the SARS-CoV-1 S protein. We also show that hydroxychloroquine efficiently blocks viral entry mediated by cathepsin L, but not by TMPRSS2, and that a combination of hydroxychloroquine and a clinically-tested TMPRSS2 inhibitor prevents SARS-CoV-2 infection more potently than either drug alone. These studies identify functional differences between SARS-CoV-1 and -2 entry processes, and provide a mechanistic explanation for the limited in vivo utility of hydroxychloroquine as a treatment for COVID-19.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2.

Ou, Tianling / Mou, Huihui / Zhang, Lizhou / Ojha, Amrita / Choe, Hyeryun / Farzan, Michael

PLoS pathogens

2021 Volume 17, Issue 1, Page(s) e1009212

Abstract	Hydroxychloroquine, used to treat malaria and some autoimmune disorders, potently inhibits viral infection of SARS coronavirus (SARS-CoV-1) and SARS-CoV-2 in cell-culture studies. However, human clinical trials of hydroxychloroquine failed to establish its usefulness as treatment for COVID-19. This compound is known to interfere with endosomal acidification necessary to the proteolytic activity of cathepsins. Following receptor binding and endocytosis, cathepsin L can cleave the SARS-CoV-1 and SARS-CoV-2 spike (S) proteins, thereby activating membrane fusion for cell entry. The plasma membrane-associated protease TMPRSS2 can similarly cleave these S proteins and activate viral entry at the cell surface. Here we show that the SARS-CoV-2 entry process is more dependent than that of SARS-CoV-1 on TMPRSS2 expression. This difference can be reversed when the furin-cleavage site of the SARS-CoV-2 S protein is ablated or when it is introduced into the SARS-CoV-1 S protein. We also show that hydroxychloroquine efficiently blocks viral entry mediated by cathepsin L, but not by TMPRSS2, and that a combination of hydroxychloroquine and a clinically-tested TMPRSS2 inhibitor prevents SARS-CoV-2 infection more potently than either drug alone. These studies identify functional differences between SARS-CoV-1 and -2 entry processes, and provide a mechanistic explanation for the limited in vivo utility of hydroxychloroquine as a treatment for COVID-19.
MeSH term(s)	Animals ; COVID-19/prevention & control ; Chlorocebus aethiops/virology ; Humans ; Hydroxychloroquine/pharmacology ; SARS-CoV-2/drug effects ; Serine Endopeptidases/drug effects ; Spike Glycoprotein, Coronavirus/drug effects ; Spike Glycoprotein, Coronavirus/metabolism ; Vero Cells/virology ; Virus Internalization/drug effects ; COVID-19 Drug Treatment
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Hydroxychloroquine (4QWG6N8QKH) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2021-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1009212
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Article ; Online: In vitro affinity maturation of broader and more-potent variants of the HIV-1-neutralizing antibody CAP256-VRC26.25.

Yin, Yiming / Quinlan, Brian D / Ou, Tianling / Guo, Yan / He, Wenhui / Farzan, Michael

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 29

Abstract: Three variable 2 (V2) loops of HIV-1 envelope glycoprotein (Env) trimer converge at the Env apex to form the epitope of an important classes of HIV-1 broadly neutralizing antibodies (bNAbs). These V2-glycan/apex antibodies are exceptionally potent but ... ...

Abstract	Three variable 2 (V2) loops of HIV-1 envelope glycoprotein (Env) trimer converge at the Env apex to form the epitope of an important classes of HIV-1 broadly neutralizing antibodies (bNAbs). These V2-glycan/apex antibodies are exceptionally potent but less broad (∼60 to 75%) than many other bNAbs. Their CDRH3 regions are typically long, acidic, and tyrosine sulfated. Tyrosine sulfation complicates efforts to improve these antibodies through techniques such as phage or yeast display. To improve the breadth of CAP256-VRC26.25 (VRC26.25), a very potent apex antibody, we adapted and extended a B cell display approach. Specifically, we used CRISPR/Cas12a to introduce VRC26.25 heavy- and light-chain genes into their respective loci in a B cell line, ensuring that each cell expresses a single VRC26.25 variant. We then diversified these loci through activation-induced cytidine deaminase-mediated hypermutation and homology-directed repair using randomized CDRH3 sequences as templates. Iterative sorting with soluble Env trimers and further randomization selected VRC26.25 variants with successively improving affinities. Three mutations in the CDRH3 region largely accounted for this improved affinity, and VRC26.25 modified with these mutations exhibited greater breadth and potency than the original antibody. Our data describe a broader and more-potent form of VRC26.25 as well as an approach useful for improving the breadth and potency of antibodies with functionally important posttranslational modifications.
MeSH term(s)	B-Lymphocytes/immunology ; Broadly Neutralizing Antibodies/chemistry ; Broadly Neutralizing Antibodies/genetics ; Broadly Neutralizing Antibodies/immunology ; HIV Antibodies/chemistry ; HIV Antibodies/genetics ; HIV Antibodies/immunology ; HIV Infections/immunology ; HIV Infections/virology ; HIV-1/genetics ; HIV-1/immunology ; Humans ; Protein Engineering ; env Gene Products, Human Immunodeficiency Virus/genetics ; env Gene Products, Human Immunodeficiency Virus/immunology
Chemical Substances	Broadly Neutralizing Antibodies ; HIV Antibodies ; env Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2021-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2106203118
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Zs.A 1148: Show issues

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Article ; Online: Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates.

He, Wenhui / Ou, Tianling / Skamangas, Nickolas / Bailey, Charles C / Bronkema, Naomi / Guo, Yan / Yin, Yiming / Kobzarenko, Valerie / Zhang, Xia / Pan, Andi / Liu, Xin / Xu, Jinge / Zhang, Lizhou / Allwardt, Ava E / Mitra, Debasis / Quinlan, Brian / Sanders, Rogier W / Choe, Hyeryun / Farzan, Michael

Immunity

2023 Volume 56, Issue 10, Page(s) 2408–2424.e6

Abstract: V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide the maturation of other bnAb classes. ... ...

Abstract	V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide the maturation of other bnAb classes. To compare antigens designed to maintain this conformation, we evaluated apex-specific responses in mice engrafted with a diverse repertoire of B cells expressing the HCDR3 of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding the improvement of VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantly in their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerized SOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineered with the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our data show that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach.
MeSH term(s)	Animals ; Mice ; HIV Antibodies ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; HIV-1 ; Antigens, Viral ; Vaccines ; env Gene Products, Human Immunodeficiency Virus ; HIV Infections ; AIDS Vaccines
Chemical Substances	HIV Antibodies ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; Antigens, Viral ; Vaccines ; env Gene Products, Human Immunodeficiency Virus ; AIDS Vaccines
Language	English
Publishing date	2023-08-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2023.07.003
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Zs.A 4227: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 69: Show issues

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Article: A more efficient CRISPR-Cas12a variant derived from

Tran, Mai H / Park, Hajeung / Nobles, Christopher L / Karunadharma, Pabalu / Pan, Li / Zhong, Guocai / Wang, Haimin / He, Wenhui / Ou, Tianling / Crynen, Gogce / Sheptack, Kelly / Stiskin, Ian / Mou, Huihui / Farzan, Michael

Molecular therapy. Nucleic acids

2021 Volume 24, Page(s) 40–53

Abstract: CRISPR effector proteins introduce double-stranded breaks into the mammalian genome, facilitating gene editing by non-homologous end-joining or homology-directed repair. Unlike the more commonly studied Cas9, the CRISPR effector protein Cas12a/Cpf1 ... ...

Abstract	CRISPR effector proteins introduce double-stranded breaks into the mammalian genome, facilitating gene editing by non-homologous end-joining or homology-directed repair. Unlike the more commonly studied Cas9, the CRISPR effector protein Cas12a/Cpf1 recognizes a T-rich protospacer adjacent motif (PAM) and can process its own CRISPR RNA (crRNA) array, simplifying the use of multiple guide RNAs. We observed that the Cas12a ortholog of
Language	English
Publishing date	2021-02-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2662631-7
ISSN	2162-2531
ISSN	2162-2531
DOI	10.1016/j.omtn.2021.02.012
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Article ; Online: Reprogramming of the heavy-chain CDR3 regions of a human antibody repertoire.

Ou, Tianling / He, Wenhui / Quinlan, Brian D / Guo, Yan / Tran, Mai H / Karunadharma, Pabalu / Park, Hajeung / Davis-Gardner, Meredith E / Yin, Yiming / Zhang, Xia / Wang, Haimin / Zhong, Guocai / Farzan, Michael

Molecular therapy : the journal of the American Society of Gene Therapy

2021 Volume 30, Issue 1, Page(s) 184–197

Abstract: B cells have been engineered ex vivo to express an HIV-1 broadly neutralizing antibody (bNAb). B cell reprograming may be scientifically and therapeutically useful, but current approaches limit B cell repertoire diversity and disrupt the organization of ... ...

Abstract	B cells have been engineered ex vivo to express an HIV-1 broadly neutralizing antibody (bNAb). B cell reprograming may be scientifically and therapeutically useful, but current approaches limit B cell repertoire diversity and disrupt the organization of the heavy-chain locus. A more diverse and physiologic B cell repertoire targeting a key HIV-1 epitope could facilitate evaluation of vaccines designed to elicit bNAbs, help identify more potent and bioavailable bNAb variants, or directly enhance viral control in vivo. Here we address the challenges of generating such a repertoire by replacing the heavy-chain CDR3 (HCDR3) regions of primary human B cells. To do so, we identified and utilized an uncharacterized Cas12a ortholog that recognizes PAM motifs present in human JH genes. We also optimized the design of 200 nucleotide homology-directed repair templates (HDRT) by minimizing the required 3'-5' deletion of the HDRT-complementary strand. Using these techniques, we edited primary human B cells to express a hemagglutinin epitope tag and the HCDR3 regions of the bNAbs PG9 and PG16. Those edited with bNAb HCDR3 efficiently bound trimeric HIV-1 antigens, implying they could affinity mature in vivo in response to the same antigens. This approach generates diverse B cell repertoires recognizing a key HIV-1 neutralizing epitope.
MeSH term(s)	Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; Epitopes/genetics ; HIV Antibodies/genetics ; HIV Infections/genetics ; HIV Infections/therapy ; HIV-1/genetics ; Humans
Chemical Substances	Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; Epitopes ; HIV Antibodies
Language	English
Publishing date	2021-11-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2010592-7
ISSN	1525-0024 ; 1525-0016
ISSN (online)	1525-0024
ISSN	1525-0016
DOI	10.1016/j.ymthe.2021.10.027
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Zs.A 5640: Show issues

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