Potent and broad neutralization of HIV-1 by a llama antibody elicited by immunization

McCoy, Laura E.; Quigley, Anna Forsman; Strokappe, Nika M.; Bulmer-Thomas, Bianca; Seaman, Michael S.; Mortier, Daniëlla; Rutten, Lucy; Chander, Nikita; Edwards, C. R. W.; Ketteler, Robin; Davis, David A.; Verrips, Theo; Weiss, Robin A.

doi:10.1084/jem.20112655

Cited by 100 publications

(136 citation statements)

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“…22 The importance of this "foreignness" is best described in a setting where camelid immunization against alien viral envelope proteins resulted in a highly diverse panel of binders, enabling targeting of multiple epitopes on the same viral envelope protein. 40,41 The camelid V family repertoire described here serves as a template to humanize camelid V genes (for therapeutic purposes) in such a way that affinity, potency and stability are retained. Finally, to fully utilize camelid IGHV, IGLV, IGKV repertoires, an optimal design of V family (member) specific primers is now made possible.…”

Section: Discussionmentioning

confidence: 99%

Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform

Klarenbeek

Mazouari²,

Desmyter

et al. 2015

mAbs

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de Haard & Ikbel Achour (2015) Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform, mAbs, 7:4, 693-706, DOI: 10.1080/19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 Camelid immunoglobulin variable (IGV) regions were found homologous to their human counterparts; however, the germline V repertoires of camelid heavy and light chains are still incomplete and their therapeutic potential is only beginning to be appreciated. We therefore leveraged the publicly available HTG and WGS databases of Lama pacos and Camelus ferus to retrieve the germline repertoire of V genes using human IGV genes as reference. In addition, we amplified IGKV and IGLV genes to uncover the V germline repertoire of Lama glama and sequenced BAC clones covering part of the Lama pacos IGK and IGL loci. Our in silico analysis showed that camelid counterparts of all human IGKV and IGLV families and most IGHV families could be identified, based on canonical structure and sequence homology. Interestingly, this sequence homology seemed largely restricted to the Ig V genes and was far less apparent in other genes: 6 therapeutically relevant target genes differed significantly from their human orthologs. This contributed to efficient immunization of llamas with the human proteins CD70, MET, interleukin (IL)-1b and IL-6, resulting in large panels of functional antibodies. The in silico predicted human-homologous canonical folds of camelidderived antibodies were confirmed by X-ray crystallography solving the structure of 2 selected camelid anti-CD70 and anti-MET antibodies. These antibodies showed identical fold combinations as found in the corresponding human germline V families, yielding binding site structures closely similar to those occurring in human antibodies. In conclusion, our results indicate that active immunization of camelids can be a powerful therapeutic antibody platform.

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Section: Discussionmentioning

confidence: 99%

Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform

Klarenbeek

Mazouari²,

Desmyter

et al. 2015

mAbs

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“…As far as we are aware, the only previous example of elicitation of broad serum neutralization and subsequent isolation of bnAbs was in llamas, when 7 immunizations with an Env trimer (not well-ordered) over 4 months resulted in poor serum neutralization breadth and potency and subsequent screening of >2,800 unique camelid-specific variable region (VHH) fragments identified only one with broad and potent neutralizing activity 25,26 .…”

Section: Main Textmentioning

confidence: 99%

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Sok

Vadnais

et al. 2017

Nature

156

198

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No immunogen to date has reliably elicited broadly neutralizing antibodies (bnAbs) to HIV in humans or animal models. Advances in the design of immunogens (BG505 SOSIP) that antigenically mimic the HIV envelope glycoprotein (Env)1 have improved the elicitation of potent isolate-specific Ab responses in rabbits2 and macaques3, but so far failed to induce bnAbs. One possible contributor to this failure is that the relevant antibody repertoires are poorly suited to target somewhat occluded conserved epitope regions on Env relative to exposed variable epitopes. To test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach over 70 amino acids in length4–9. Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 cross-clade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody (mAb) isolated from this cow harbored an ultralong HCDR3 of 60 amino acids and neutralized 72% of cross-clade isolates (n = 117) with a potent median IC50 of 0.028 μg/ml. We note that breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.

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“…To directly consider the impact of size on neutralisation by J3, J3 VHH DNA was cloned upstream of a human immunoglobulin (IgG) CH2-CH3 region (J3-Fc), expressed in HEK 293 cells and purified by affinity to protein A. This process allowed reconstruction of J3 into the original heavy chain only format in which it was elicited in response to immunisation [22] but with a human Fc region. First we assessed cell-free neutralisation by J3 and J3-Fc against a panel of viruses that were either sensitive or resistant to neutralisation by the VHH J3 monomer in the TZM-bl assay ( Figure 4A).…”

Section: Efficient Neutralisation By J3 Is Not Dependent On Antibody mentioning

confidence: 99%

“…However, there are differences in the ability of anti-CD4 binding site antibodies to neutralise HIV-1 both in terms of breadth and potency, reflecting their maturation in different hosts in response to diverse stimuli and specific isolation methods. Recent advances in isolating and eliciting of bNAbs against HIV-1 has led to the identification of a number of new broad and potent antibodies targeting the CD4 binding site including VRC01, HJ16 and J3 [22][23][24]. J3 is particularly interesting because unlike other broad and potent antibodies that were isolated from HIV-1 infected individuals, J3 is a HCAb variable region (VHH) that was isolated from a llama immunised with recombinant gp140 from subtypes A and B/C [22].…”

Section: Introductionmentioning

confidence: 99%

“…Recent advances in isolating and eliciting of bNAbs against HIV-1 has led to the identification of a number of new broad and potent antibodies targeting the CD4 binding site including VRC01, HJ16 and J3 [22][23][24]. J3 is particularly interesting because unlike other broad and potent antibodies that were isolated from HIV-1 infected individuals, J3 is a HCAb variable region (VHH) that was isolated from a llama immunised with recombinant gp140 from subtypes A and B/C [22]. Llamas and other camelids contain HCAbs of approximately 82 KDa in addition to conventional antibodies of approximately 145 KDa [25].…”

Section: Introductionmentioning

confidence: 99%

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Neutralisation of HIV-1 cell-cell spread by human and llama antibodies

et al. 2014

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Background: Direct cell-cell spread of HIV-1 is a very efficient mode of viral dissemination, with increasing evidence suggesting that it may pose a considerable challenge to controlling viral replication in vivo. Much current vaccine research involves the study of broadly neutralising antibodies (bNabs) that arise during natural infection with the aims of eliciting such antibodies by vaccination or incorporating them into novel therapeutics. However, whether cell-cell spread of HIV-1 can be effectively targeted by bNabs remains unclear, and there is much interest in identifying antibodies capable of efficiently neutralising virus transmitted by cell-cell contact. Results:In this study we have tested a panel of bNAbs for inhibition of cell-cell spread, including some not previously evaluated for inhibition of this mode of HIV-1 transmission. We found that three CD4 binding site antibodies, one from an immunised llama (J3) and two isolated from HIV-1-positive patients (VRC01 and HJ16) neutralised cell-cell spread between T cells, while antibodies specific for glycan moieties (2G12, PG9, PG16) and the MPER (2F5) displayed variable efficacy. Notably, while J3 displayed a high level of potency during cell-cell spread we found that the small size of the llama heavy chain-only variable region (VHH) J3 is not required for efficient neutralisation since recombinant J3 containing a full-length human heavy chain Fc domain was significantly more potent. J3 and J3-Fc also neutralised cell-cell spread of HIV-1 from primary macrophages to CD4+ T cells.

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Potent and broad neutralization of HIV-1 by a llama antibody elicited by immunization

Abstract: A heavy chain–only antibody isolated from a llama repeatedly immunized with trimeric HIV-1 Env neutralizes 96% of tested HIV-1 strains.

Cited by 100 publications

References 61 publications

Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform

Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Neutralisation of HIV-1 cell-cell spread by human and llama antibodies

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