Coming together at the hinges: Therapeutic prospects of IgG3

Chu, Thach H.; Patz, Edward F.; Ackerman, Margaret E.

doi:10.1080/19420862.2021.1882028

Cited by 40 publications

(54 citation statements)

References 174 publications

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“…Spike-specific FcγR-binding antibodies made frequent contributions to models of effector functions, with FcgRIIa contributing strongly to phagocytosis and FcgRIIIa contributing strongly to NK cell activity. Among subclasses, IgG3 made an outsized contribution, consistent with prior studies in the context of other infections [59][60][61] , and monoclonal antibody subclass-switching studies 47,48 . In contrast, virus-specific IgM contributed to predictions of neutralization activity.…”

Section: Discussionsupporting

confidence: 82%

Antibody Attributes that Predict the Neutralization and Effector Function of Polyclonal Responses to SARS-CoV-2

Natarajan

Crowley

et al. 2021

Preprint

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While antibodies provide significant protection from SARS-CoV-2 infection and disease sequelae, the specific attributes of the humoral response that contribute to immunity are incompletely defined. In this study, we employ machine learning to relate characteristics of the polyclonal antibody response raised by natural infection to diverse antibody effector functions and neutralization potency with the goal of generating both accurate predictions of each activity based on antibody response profiles as well as insights into antibody mechanisms of action. To this end, antibody-mediated phagocytosis, cytotoxicity, complement deposition, and neutralization were accurately predicted from biophysical antibody profiles in both discovery and validation cohorts. These predictive models identified SARS-CoV-2-specific IgM as a key predictor of neutralization activity whose mechanistic relevance was supported experimentally by depletion. Validated models of how different aspects of the humoral response relate to antiviral antibody activities suggest desirable attributes to recapitulate by vaccination or other antibody-based interventions.

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Section: Discussionsupporting

confidence: 82%

Antibody Attributes that Predict the Neutralization and Effector Function of Polyclonal Responses to SARS-CoV-2

Natarajan

Crowley

et al. 2021

Preprint

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“…pH Dependence for Binding to the Neonatal Fc Receptor Is Similar for IgG1 and IgG3 bNAbs That Use a Lambda Light Chain One of the major reasons that IgG3 is not widely considered for therapeutic use is that it has a reduced half-life of approximately 7 days compared to that of 21 days for IgG1 (41). It is known that the reduced pH dependence of IgG3 compared to IgG1 is the major contributor to poor half-life, with antibody binding to FcRn being a good proxy of half-life (39).…”

Section: Fcg Receptor Binding Is Enhanced By Igg3mentioning

confidence: 99%

“…IgG3 is highly polymorphic with 29 reported alleles (37), and this variability is known to alter antibody activity and half-life (34,38,39). Structurally, IgG3 is distinct from other subclasses, with a long flexible hinge, enabling high rotational freedom about the Fc-Fab and Fab-Fab axes (40,41). In HIV infection, skewing towards IgG3 has been associated with reduced risk of infection in the RV144 and HVTN 505 vaccine trials (14,15,42) and in viral control (11).…”

Section: Introductionmentioning

confidence: 99%

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HIV Broadly Neutralizing Antibodies Expressed as IgG3 Preserve Neutralization Potency and Show Improved Fc Effector Function

et al. 2021

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The ability of several broadly neutralizing antibodies (bNAbs) to protect against HIV infection is enhanced through Fc receptor binding. Antibody isotype modulates this effect, with IgG3 associated with improved HIV control and vaccine efficacy. We recently showed that an IgG3 variant of bNAb CAP256-VRC26.25 exhibited more potent neutralization and phagocytosis than its IgG1 counterpart. Here, we expanded this analysis to include additional bNAbs targeting all major epitopes. A total of 15 bNAbs were expressed as IgG1 or IgG3, and pairs were assessed for neutralization potency against the multi-subtype global panel of 11 HIV strains. Binding to the neonatal Fc receptor (FcRn) and Fcγ receptors were measured using ELISA and antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis were measured using infectious viruses and global panel Env SOSIP trimers, respectively. IgG3 bNAbs generally showed similar or increased (up to 60 fold) neutralization potency than IgG1 versions, though the effect was virus-specific. This improvement was statistically significant for CAP256-VRC26.25, 35022, PGT135 and CAP255.G3. IgG3 bNAbs also showed significantly improved binding to FcγRIIa which correlated with enhanced phagocytosis of all trimeric Env antigens. Differences in ADCC were epitope-specific, with IgG3 bNAbs to the MPER, CD4 binding site and gp120-gp41 interface showing increased ADCC. We also explored the pH dependence of IgG1 and IgG3 variants for FcRn binding, as this determines the half-life of antibodies. We observed reduced pH dependence, associated with shorter half-lives for IgG3 bNAbs, with κ-light chains. However, IgG3 bNAbs that use λ-light chains showed similar pH dependence to their IgG1 counterparts. This study supports the manipulation of the constant region to improve both the neutralizing and Fc effector activity of bNAbs, and suggests that IgG3 versions of bNAbs may be preferable for passive immunity given their polyfunctionality.

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“…Consequently, IgG1 or IgG3 mAb 830A provided no advantage in protection against SHIV SF162P3 in macaques ( 124 ). The prospect of subclass switching to convert bNAbs into IgG3 antibodies is gaining some traction as another approach to improve Ab-driven effective humoral immune responses, and further exploration with IgG3 in a preclinical setting has been suggested ( 125 ) especially where effector functions could complement or augment neutralization.…”

Section: Cultivating Bnab Development For Treatment and Preventionmentioning

confidence: 99%

Advancing HIV Broadly Neutralizing Antibodies: From Discovery to the Clinic

Spencer

Shapiro

Haigwood

et al. 2021

Front. Public Health

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Despite substantial progress in confronting the global HIV-1 epidemic since its inception in the 1980s, better approaches for both treatment and prevention will be necessary to end the epidemic and remain a top public health priority. Antiretroviral therapy (ART) has been effective in extending lives, but at a cost of lifelong adherence to treatment. Broadly neutralizing antibodies (bNAbs) are directed to conserved regions of the HIV-1 envelope glycoprotein trimer (Env) and can block infection if present at the time of viral exposure. The therapeutic application of bNAbs holds great promise, and progress is being made toward their development for widespread clinical use. Compared to the current standard of care of small molecule-based ART, bNAbs offer: (1) reduced toxicity; (2) the advantages of extended half-lives that would bypass daily dosing requirements; and (3) the potential to incorporate a wider immune response through Fc signaling. Recent advances in discovery technology can enable system-wide mining of the immunoglobulin repertoire and will continue to accelerate isolation of next generation potent bNAbs. Passive transfer studies in pre-clinical models and clinical trials have demonstrated the utility of bNAbs in blocking or limiting transmission and achieving viral suppression. These studies have helped to define the window of opportunity for optimal intervention to achieve viral clearance, either using bNAbs alone or in combination with ART. None of these advances with bNAbs would be possible without technological advancements and expanding the cohorts of donor participation. Together these elements fueled the remarkable growth in bNAb development. Here, we review the development of bNAbs as therapies for HIV-1, exploring advances in discovery, insights from animal models and early clinical trials, and innovations to optimize their clinical potential through efforts to extend half-life, maximize the contribution of Fc effector functions, preclude escape through multiepitope targeting, and the potential for sustained delivery.

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Coming together at the hinges: Therapeutic prospects of IgG3

Cited by 40 publications

References 174 publications

Antibody Attributes that Predict the Neutralization and Effector Function of Polyclonal Responses to SARS-CoV-2

Antibody Attributes that Predict the Neutralization and Effector Function of Polyclonal Responses to SARS-CoV-2

HIV Broadly Neutralizing Antibodies Expressed as IgG3 Preserve Neutralization Potency and Show Improved Fc Effector Function

Advancing HIV Broadly Neutralizing Antibodies: From Discovery to the Clinic

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