DrJiaGuo

Rijal P, Elias SC, Machado SR, Xiao J, Schimanski L, O'Dowd V, Baker T, Barry E, Mendelsohn SC, Cherry CJ, Jin J, Labbé GM, Donnellan FR, Rampling T, Dowall S, Rayner E, Findlay-Wilson S, Carroll M, Guo J, Xu XN, Huang KYA, Takada A, Burgess G, McMillan D, Popplewell A, Lightwood DJ, Draper SJ, Townsend ARet al., 2019, Therapeutic monoclonal antibodies for Ebola virus infection derived from vaccinated humans, Cell Reports, Vol: 27, Pages: 172-186.e7, ISSN: 2211-1247

We describe therapeutic monoclonal antibodies isolated from human volunteers vaccinated with recombinant adenovirus expressing Ebola virus glycoprotein (EBOV GP) and boosted with modified vaccinia virus Ankara. Among 82 antibodies isolated from peripheral blood B cells, almost half neutralized GP pseudotyped influenza virus. The antibody response was diverse in gene usage and epitope recognition. Although close to germline in sequence, neutralizing antibodies with binding affinities in the nano- to pico-molar range, similar to “affinity matured” antibodies from convalescent donors, were found. They recognized the mucin-like domain, glycan cap, receptor binding region, and the base of the glycoprotein. A cross-reactive cocktail of four antibodies, targeting the latter three non-overlapping epitopes, given on day 3 of EBOV infection, completely protected guinea pigs. This study highlights the value of experimental vaccine trials as a rich source of therapeutic human monoclonal antibodies.

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Wu X, Guo J, Niu M, An M, Liu L, Wang H, Jin X, Zhang Q, Lam KS, Wu T, Wang H, Wang Q, Du Y, Li J, Cheng L, Tang HY, Shang H, Zhang L, Zhou P, Chen Zet al., 2018, Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice, Journal of Clinical Investigation, Vol: 128, Pages: 2239-2251, ISSN: 0021-9738

The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral therapy (cART). Here, we investigate the potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving 2 single-chain variable fragment (scFv) binding domains of each parental bnAb, a single gene–encoded tandem bs-bnAb, BiIA-SG, displayed substantially improved breadth and potency. BiIA-SG neutralized all 124 HIV-1–pseudotyped viruses tested, including global subtypes/recombinant forms, transmitted/founder viruses, variants not susceptible to parental bnAbs and to many other bnAbs with an average IC50 value of 0.073 μg/ml (range < 0.001–1.03 μg/ml). In humanized mice, an injection of BiIA-SG conferred sterile protection when administered prior to challenges with diverse live HIV-1 stains. Moreover, whereas BiIA-SG delayed viral rebound in a short-term therapeutic setting when combined with cART, a single injection of adeno-associated virus–transferred (AAV-transferred) BiIA-SG gene resulted dose-dependently in prolonged in vivo expression of BiIA-SG, which was associated with complete viremia control and subsequent elimination of infected cells in humanized mice. These results warrant the clinical development of BiIA-SG as a promising bs-bnAb–based biomedical intervention for the prevention and treatment of HIV-1 infection.

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Tang X, Guo J, Cheng L, Sun C, Liu L, Zuo T, Wang H, Chen L, Zhang L, Chen Zet al., 2017, Single N277A substitution in C2 of simian immunodeficiency virus envelope influences vaccine-elicited CD4i neutralizing and anti-V2 antibody responses, Vaccine, Vol: 35, Pages: 2582-2591, ISSN: 0264-410X

An effective HIV vaccine remains elusive, and immunogens capable of eliciting protective host humoral immunity have not yet been identified. Although HIV/SIV infections result in the abundant production of CD4-induced (CD4i) antibodies (Abs), these Abs are not protective due to steric restrictions following gp120 binding to CD4 on target cells. Here we report that both DNA- and vaccinia-based vaccines encoding SIVmac239 gp160 readily elicited high levels of CD4i Abs in experimental animals. We identified a highly conserved N-linked glycosylation site N277 in the C2 region which strongly affected the immunogenicity of the CD4i Ab domain. Moreover, a single N277A substitution significantly enhanced the immunogenicity of the V2 domain yielding higher titers and frequency of anti-V2 Ab responses as determined by ELISA and yeast antigen display mapping, respectively. Importantly, immune sera elicited by the N277A-mutated gp160 exhibited elevated antibody-dependent cellular cytotoxicity (ADCC) activity. ADCC activity correlated positively with the anti-V2 Ab titer yet, inversely with CD4i Ab titer. Thus, we identified a determinant of the CD4i domain that might affect vaccine-elicited anti-V2 Ab and ADCC responses to SIVmac239. Our findings may have implications for design of immunogens to direct B cell recognition in the development of an Ab-based HIV vaccine.

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McFaul K, Guo J, Atkins E, Xu X-N, Kelleher Pet al., 2016, A novel method to assess the functional of the anti-HIV gp-41 antibody in acute HIV-1 infection, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 27-27, ISSN: 1464-2662

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Cheng L, Tang X, Liu L, Peng J, Nishiura K, Cheung AKL, Guo J, Wu X, Tang HY, An M, Zhou J, Cheung KW, Wang H, Guan X, Wu Z, Chen Zet al., 2015, Monoclonal antibodies specific to human Δ42PD1: A novel immunoregulator potentially involved in HIV-1 and tumor pathogenesis, mAbs, Vol: 7, Pages: 620-629, ISSN: 1942-0862

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Guo J, Zuo T, Cheng L, Wu X, Tang J, Sun C, Feng L, Chen L, Zhang L, Chen Zet al., 2015, Simian Immunodeficiency Virus Infection Evades Vaccine-Elicited Antibody Responses to V2 Region, JAIDS Journal of Acquired Immune Deficiency Syndromes, Vol: 68, Pages: 502-510, ISSN: 1525-4135

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Kang Y, Guo J, Chen Z, 2013, Closing the door to human immunodeficiency virus, Protein & Cell, Vol: 4, Pages: 86-102, ISSN: 1674-800X

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