Broadly Neutralizing Antibodies as Treatment: Effects on Virus and Immune System

Purpose of Review

The purpose of this study is to summarize recent advances in the use of broadly neutralizing antibodies (bNAbs) as therapeutics in human clinical trials and in non-human primate (NHP) models. We seek to highlight lessons from these studies with an emphasis on consequences to the virus and immune system.

Recent Findings

In the past 10 years, advances in HIV-1 trimer structure and B cell isolation methods have precipitated the identification of “new-generation” anti-HIV antibodies with broad and potent neutralization. In the past 2 years, the concept of using these bNAbs as therapeutic tools has moved from NHP models into human clinical trials. These trials have investigated the effects of bNAb infusions into patients chronically infected with HIV-1, while the NHP model has investigated treatment during acute infection.

Summary

Through this work, the relationship between in vitro breadth and potency and in vivo clinical effect, although unresolved, is gradually being elucidated. These results emphasize the need for combination antibody therapy.

     

Neutralizing Antibodies and Control of HIV: Moves and Countermoves

It is now evident that powerful antibodies directed to conserved regions of HIV-1 envelope protein develop during chronic infection in some individuals and that these antibodies can neutralize a broad array of diverse isolates in vitro, so termed broadly neutralizing antibodies (bNAbs). A great deal of effort is directed internationally at understanding the ontogeny of NAbs during infection as well as in designing and testing immunogens that can elicit bNAbs in animal models and in humans. Given the parrying tactics of Env, multiple approaches, along with high-resolution structural studies, will be needed to reach a degree of understanding sufficient to design an effective vaccine. We discuss and note here some of the most important recent advances in our knowledge of how neutralizing antibodies develop in vivo, the recent discovery of extremely powerful neutralizing monoclonal antibodies isolated from natural infection, enhanced methodologies that have accelerated discoveries on both fronts, and the progress made in eliciting potent NAbs with limited breadth by vaccination.     

An Antigenic Atlas of HIV-1 Escape from Broadly Neutralizing Antibodies Distinguishes Functional and Structural Epitopes

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Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope

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HIV Reservoirs and Strategies for Eradication

Combination antiretroviral therapy (cART) has led to a reduction in morbidity and mortality in HIV-infected patients but therapy is lifelong and there is no cure for HIV. The major barriers to cure include HIV latency, which has been identified in different T-cell subsets, as well as persistence of HIV in anatomical reservoirs. We review recent developments in our understanding of the major reservoirs of HIV in patients on cART as well as how latency is established and maintained in T cells. Finally, we review the scientific rationale of and clinical experience with pharmacotherapeutic strategies aimed at eliminating latently infected cells.     

Influenza Virus-Specific Neutralizing IgM Antibodies Persist for a Lifetime

Detection of immunoglobulin M (IgM) antibodies has long been used as an important diagnostic tool for identifying active viral infections, but their relevance in later stages has not been clearly defined in vivo. In this study, we followed the kinetics, longevity, and function of influenza virus-specific IgM antibodies for 2 years following sublethal infection of mice with live mouse-adapted A/PR/8/34 virus or immunization with formalin-inactivated virus. These groups mounted robust protective immune responses and survived lethal challenges with 50× 50% lethal dose (LD₅₀) mouse-adapted A/PR/8/34 virus 600 days after the primary exposure. Surprisingly, the virus-specific IgM antibodies persisted along with IgG antibodies, and we found a significantly higher number of IgM-positive (IgM⁺) virus-specific plasma cells than IgG⁺ plasma cells that persisted for at least 9 months postexposure. The IgM antibodies were functional as they neutralized influenza virus in the presence of complement just as well as IgG antibodies did.     

Progress on the Induction of Neutralizing Antibodies Against HIV Type 1 (HIV-1)

Infection with HIV type 1 (HIV-1), the causative agent of AIDS, is one of the most catastrophic pandemics to affect human healthcare in the latter 20th century. The best hope of controlling this pandemic is the development of a successful prophylactic vaccine. However, to date, this goal has proven to be exceptionally elusive. The recent failure of an experimental vaccine in a phase IIb study, named the STEP trial, intended solely to elicit cell-mediated immune responses against HIV-1, has highlighted the need for a balanced immune response consisting of not only cellular immunity but also a broad and potent humoral antibody response that can prevent infection with HIV-1. This article reviews the efforts made up to this point to elicit such antibody responses, especially with regard to the use of a DNA prime-protein boost regimen, which has been proven to be a highly effective platform for the induction of neutralizing antibodies in both animal and early-phase human studies.     

Neutralizing Anti-Influenza Virus Monoclonal Antibodies: Therapeutics and Tools for Discovery

The human antibody response to influenza virus infection plays a protective role against re-infection, yet little molecular detail is available regarding how human antibodies, when characterized at the monoclonal level, neutralize this important human pathogen. Recent studies, using a diverse array of strategies, have isolated and characterized human anti-virus neutralizing antibodies and shed light not only on the specificity and origin of these antibodies but on their potential for therapeutic use against influenza virus infection.     

Mapping Broadly Reactive Norovirus Genogroup I and II Monoclonal Antibodies

Noroviruses are responsible for most acute nonbacterial epidemic outbreaks of gastroenteritis worldwide. To develop cross-reactive monoclonal antibodies (MAbs) for rapid identification of genogroup I and II (GI and GII) noroviruses (NoVs) in field specimens, mice were immunized with baculovirus-expressed recombinant virus-like particles (VLPs) corresponding to NoVs. Nine MAbs against the capsid protein were identified that detected both GI and GII NoV VLPs. These MAbs were tested in competition enzyme-linked immunosorbent assays (ELISAs) to identify common epitope reactivities to GI and GII VLPs. Patterns of competitive reactivity placed these MAbs into two epitope groups (groups 1 and 2). Epitopes for MAbs NV23 and NS22 (group 1) and MAb F120 (group 2) were mapped to a continuous region in the C-terminal P1 subdomain of the capsid protein. This domain is within regions previously defined to contain cross-reactive epitopes in GI and GII viruses, suggesting that common epitopes are clustered within the P1 domain of the capsid protein. Further characterization in an accompanying paper (B. Kou et al., Clin Vaccine Immunol 22:160–167, 2015, http://dx.doi.org/10.1128/CVI.00519-14) revealed that MAb NV23 (epitope group 1) is able to detect GI and GII viruses in stool. Inclusion of the GI and GII cross-reactive MAb NV23 in antigen detection assays may facilitate the identification of GI and GII human noroviruses in stool samples as causative agents of outbreaks and sporadic cases of gastroenteritis worldwide.     

Immunotherapeutic Approaches for the Control and Eradication of HIV

Since the onset of the AIDS epidemic over 35 years ago, attempts at immunologic manipulation to develop preventative and therapeutic approaches to HIV infection have been the subject of intense focus by the scientific community. New tactics such as latency reveal agents and immune interventions with engineered and directed monoclonal antibodies, as well as vaccines for prevention and treatment are among the strategies addressed in this review.     

人群中腺病毒中和抗体调查

对北京、南京、成都、海口四市１２５３份不同年龄组人群中４，７型腺病毒中和抗体进行了调查。结果，人群中４，７型腺病毒总阳性率分别为３１．０，２２．２％。不同城市人群腺病毒抗体阳性率不一，北京地区高于其他地区。７型腺病毒抗体阳性率有由南往北逐渐增高的现象，表明北方７型腺病毒感染多于南方。     

Development and Validation of a Quasi-Quantitative Bioassay for Neutralizing Antibodies Against CP-870,893

The human monoclonal antibody CP-870,893 is a CD40 receptor agonist currently being developed for the treatment of cancer. A bioassay to measure neutralizing antibodies (Nab) to CP-870,893 in 5% human serum matrix was developed and validated utilizing the Daudi cell line and flow cytometric detection. Additionally, samples from CP-870,893 treated cynomolgus monkeys were analyzed in the bioassay and compared to results obtained using a competitive receptor-binding (CRB) Nab immunoassay to determine if the CRB assay may be used in place of the bioassay. Treatment of Daudi cells for 2 d with CP-870,893 leads to a concentration-dependent increase in CD54 cell surface expression. The presence of antidrug Nab attenuates CP-870,893 binding to CD40 and the induction of CD54. An anti-idiotype monoclonal antibody (Mab) and a monkey sera pool were identified as positive controls for neutralization of CP-870,893. During development, it was observed that the assay robustness was altered by culture media and FBS substitutions. For validation the following parameters were established: cutpoint factors in the presence (0.779) and absence (1.282) of 50 ng/ml CP-870,893, linear region of the concentration-response (1-100 ng/ml CP-870,893), intra- and inter-assay precision (CV 相似文献   

Neutralizing Antibodies to Cytomegaloviruses in Normal Simian and Human Sera

Simian and human sera were examined for neutralizing antibodies to simian and human cytomegaloviruses (CMV). Neutralizing antibody to simian CMV was found in sera from 12 of 12 African green monkeys, 8 of 10 rhesus monkeys, and 7 of 7 baboons captured in the wild. The antibody did not cross-react with human CMV strain AD169 but cross-reacted with human strain C87, particularly in the presence of complement. Thirty-six baboons and 10 rhesus monkeys born and hand-reared in captivity remained free of neutralizing antibody both to simian and human CMV for as long as 4 years. Fifteen of 24 human sera (63%) revealed only species-specific neutralizing antibody.     

Evaluation of Antibodies against a Rubella Virus Neutralizing Domain for Determination of Immune Status

The protective immune responses against rubella virus (RV) are related to its neutralizing epitopes, an issue that is important to consider when assessing the immune status of patients with remote infection. In the present paper, we compare the antibodies detected by a synthetic-peptide-based enzyme immunoassay (EIA) with antibodies detected by the traditional technique of hemagglutination inhibition (HIA) in patients with remote RV infection. The synthetic peptide used as an antigen (SP15) represents a neutralizing epitope that corresponds to amino acids 208 to 239 of the E1 glycoprotein. The SP15-EIA was developed, all variables that affected the assay were standardized, and the test was validated using reference sera. Serum samples (n = 129) from patients with remote RV infection were tested by HIA and SP15-EIA. Discrepant sera were assayed by MEIA (IMX/Abbot). The comparison between HIA and SP15-EIA, taking HIA as the standard methodology for determining immune status, showed that SP15-EIA is very specific and sensitive for detecting protecting antibodies (specificity, 100%; sensitivity, 98.20%). This study demonstrates that antibodies against the neutralizing domain represented by SP15 would be important in the memory response after natural infection and may be a good tool in the determination of the true immune status of patients with remote infection with regard to RV.