Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial

Gaudinski, Martin R.; Houser, Katherine V.; Doria‐Rose, Nicole A.; Chen, Grace L.; Rothwell, Ro Shauna; Berkowitz, Nina M.; Costner, Pamela; Holman, LaSonji A.; Gordon, Ingelise J.; Hendel, Cynthia S.; Kaltovich, Florence; Conan-Cibotti, Michelle; Lorenzo, Margarita Gomez; Carter, Cristina; Sitar, Sandra; Carlton, Kevin; Gall, Jason; Laurençot, Carolyn M.; Lin, Bob C.; Bailer, Robert T.; McDermott, Adrian B.; Ko, Sung-Youl; Pegu, Amarendra; Kwon, Young Do; Kwong, Peter D.; Namboodiri, Aryan M.; Pandey, Janardan P.; Schwartz, Richard; Arnold, Frank; Hu, Zonghui; Zhang, Lily; Huang, Yunda; Koup, Richard A.; Capparelli, Edmund V.; Graham, Barney S.; Mascola, John R.; Ledgerwood, Julie E.; Mendoza, Floreliz; Novik, Laura; Zephir, Kathy; Whalen, William; Larkin, Brenda; Saunders, Jamie; Cunningham, Jennifer; Levinson, Carol; Wang, Xiaolin; Plummer, Sarah H.; Victorino, Milalynn; Ola, Abidemi; Boyd, Catina R.; Jayasinghe, Nilusha; Apte, Preeti; Cartagena, Cora Trelles; Hicks, Renunda; Williams, Pernell; Василенко, О. А.; Yamshchikov, Galina V.; Florez, Maria Burgos; Pittman, Iris; Gama, Lúcio; Casazza, Joseph P.; Decederfelt, Hope; Cheng, K.-C.; Stein, Judy

doi:10.1016/s2352-3018(19)30181-x

Cited by 72 publications

(57 citation statements)

References 30 publications

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“…Accordingly, all CD4bs bNAbs that have advanced into clinical testing are members of the VRC01 class (3BNC117, N6, VRC01, and VRC07-523) (Bar et al, 2016; Bar-On et al, 2018;Caskey et al, 2015Caskey et al, , 2019Cohen et al, 2018a;Crowell et al, 2019;Gaudinski et al, 2018Gaudinski et al, , 2019Gruell and Klein, 2018;Ledgerwood et al, 2015;Lynch et al, 2015a;Mayer et al, 2017;Mendoza et al, 2018;Riddler et al, 2018;Scheid et al, 2016). However, although escape from VRC01 has been associated with a reduction in viral fitness (Lynch et al, 2015b), the effects of VRC01class monotherapy are only transient and associated with emergence of viral escape variants (Bar et al, 2016;Caskey et al, 2015;Horwitz et al, 2013;Klein et al, 2012;Lynch et al, 2015a;Scheid et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Schommers

Gruell

Abernathy

et al. 2020

Cell

111

155

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Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new V H 1-46encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC 50 = 0.048 mg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505 SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.

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Section: Introductionmentioning

confidence: 99%

Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Schommers

Gruell

Abernathy

et al. 2020

Cell

111

155

View full text Add to dashboard Cite

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“…VRC01LS displayed a favourable safety in HIV-negative healthy adults, and the results revealed that its serum half-life was 71 ± 18 days after intravenous administration, more than 4-fold greater than wild-type VRC01 [36]. Additionally, an engineered version of VRC07, VRC07-523LS, has been demonstrated to be safe and shown improved pharmacokinetic and neutralization properties relative to VRC01 and VRC01LS in a phase 1 clinical trial [37]. VRC07-523LS administered alone or concurrently with other bNAbs, including 10E8VLS, PGT121, 10-1074 and PGDM1400, has also been advanced to additional clinical trials (NCT03387150, NCT03735849, NCT02256631, NCT02840474, NCT03565315, NCT03721510, and NCT03928821).…”

Section: Efficacy Of Next-generation Bnabs In Clinical Trialsmentioning

confidence: 99%

Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities

Liu

Cao

Sun

et al. 2020

Emerging Microbes & Infections

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Combination antiretroviral therapy (cART) is effective but not curative, and no successful vaccine is currently available for human immunodeficiency virus-1 (HIV-1). Broadly neutralizing antibodies (bNAbs) provide a new approach to HIV-1 prevention and treatment, and these promising candidates advancing into clinical trials have shown certain efficacies in infected individuals. In addition, bNAbs have the potential to kill HIV-1-infected cells and to affect the course of HIV-1 infection by directly engaging host immunity. Nonetheless, challenges accompany the use of bNAbs, including transient suppression of viraemia, frequent emergence of resistant viruses in rebound viraemia, suboptimal efficacy in virus cell-tocell transmission, and unclear effects on the cell-associated HIV-1 reservoir. In this review, we discuss opportunities and potential strategies to address current challenges to promote the future use of immunotherapy regimens.

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“…Due to these results, it is not surprising that the LS mutations have been included in evaluating the safety of bNAbs in clinical trials. LS versions VRC01 and VRC07-523 have been evaluated in the clinic and have reported half-lives of 71 and 38 days, respectively (Gaudinski et al, 2018(Gaudinski et al, , 2019. Having measurable quantities of bNAbs in the blood for longer periods of time would presumably lead to less frequent dosing, and ultimately, lower the cost of production.…”

Section: Learning From Passive Infusion Efficacy Studies Preclinical mentioning

confidence: 99%

Promise and Progress of an HIV-1 Cure by Adeno-Associated Virus Vector Delivery of Anti-HIV-1 Biologics

Gardner

2020

Front. Cell. Infect. Microbiol.

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Despite the success of antiretroviral therapy (ART) at suppressing HIV-1 infection, a cure that eradicates all HIV-1-infected cells has been elusive. The latent viral reservoir remains intact in tissue compartments that are not readily targeted by the host immune response that could accelerate the rate of reservoir decline during ART. However, over the past decade, numerous broadly neutralizing antibodies (bNAbs) have been discovered and characterized. These bNAbs have also given rise to engineered antibody-like inhibitors that are just as or more potent than bNAbs themselves. The question remains whether bNAbs and HIV-1 inhibitors will be the effective "kill" to a shock-and-kill approach to eliminate the viral reservoir. Additional research over the past few years has sought to develop recombinant adeno-associated virus (rAAV) vectors to circumvent the need for continual administration of bNAbs and maintain persistent expression in a host. This review discusses the advancements made in using rAAV vectors for the delivery of HIV-1 bNAbs and inhibitors and the future of this technology in HIV-1 cure research. Numerous groups have demonstrated with great efficacy that rAAV vectors can successfully express protective concentrations of bNAbs and HIV-1 inhibitors. Yet, therapeutic concentrations, especially in non-human primate (NHP) models, are not routinely achieved. As new studies have been reported, more challenges have been identified for utilizing rAAV vectors, specifically how the host immune response limits the attainable concentrations of bNAbs and inhibitors. The next few years should provide improvements to rAAV vector delivery that will ultimately show whether they can be used for expressing bNAbs and HIV-1 inhibitors to eliminate the HIV-1 viral reservoir.

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Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial

Cited by 72 publications

References 30 publications

Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities

Promise and Progress of an HIV-1 Cure by Adeno-Associated Virus Vector Delivery of Anti-HIV-1 Biologics

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