The potential clinical benefit of the Multabody platform as a therapeutic for SARS-CoV-2

In a recent article published in the Science Translational Medicine Journal, researchers demonstrated that combining the avidity and specificity of traditional monoclonal antibodies (MAbs) could expand their neutralization breadth and resilience against viral diversity using a multi-specific, multi-affinity antibody (Multabody, MB) platform derived from the human apoferritin protomer.

Study: A multi-specific, multi-affinity antibody platform neutralizes sarbecoviruses and confers protection against SARS-CoV-2 in vivo. Image Credit: CoronaBorealisStudio/Shutterstock.comStudy: A multi-specific, multi-affinity antibody platform neutralizes sarbecoviruses and confers protection against SARS-CoV-2 in vivo. Image Credit: CoronaBorealisStudio/Shutterstock.com

Background

The MB platform coupled enhanced affinity to multi-specificity, i.e., aggregation of several antibody fragments recognizing different epitopes for antigen recognition that remain unperturbed by viral mutations.

Further, they tested whether the MB platform conferred in vivo protection against different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) and other coronaviruses (CoVs) at low doses.

The REGEN-COV cocktail received United States Food and Drug Administration (U.S.-FDA) authorization to treat coronavirus disease 2019 (COVID-19). However, after the rise of the Omicron BA.1, FDA revoked their authorization.

With the advent of Omicron subvariants, BQ.1.1 and XBB.1, FDA revoked the authorizations of mAbs that effectively neutralized Omicron, including bebtelovimab.

Since most FDA-authorized mAb therapies have gradually lost efficacy against the Omicron subvariants, there is an urgent unmet medical need for novel, more effective mAb therapeutics for SARS-CoV-2 with augmented potency and broad activity but effective at the reduced therapeutic dose(s).

In addition, mAbs for SARS-CoV-2 should become available at a reduced cost to meet global demands. Thus, researchers need to find strategies for alternative routes of administration for SARS-CoV-2 mAbs, such as subcutaneous or intramuscular delivery.

In this regard, adopting an approach based on increasing antibody valency could help enhance a mAbs binding affinity, thus, potentially lowering its therapeutic dosage, improving the neutralization breadth, and enabling administration through other routes.

Researchers have discovered several antibody engineering strategies to exploit avidity to enhance the functional responses of therapeutic mAbs. Of note, a phase I/II clinical trial is testing the efficacy of GEN3009, INBRX-106, and IGM-8444 against hematological and solid tumors, thus, highlighting the clinical relevance/benefits of MB-like platforms.

About this study

Based on the same principle, researchers developed the MB platform to increase the neutralization potency of SARS-CoV-2 targeting mAbs; however, they used the human light-chain apoferritin protomer to drive the oligomerization of antibody fragments.

The primary study objective was to validate that the MB format overcame viral diversity through all the potent antibodies it comprised.

The researchers determined potency by in vitro neutralization assays using pseudoviruses (PsV) or authentic SARS-CoV-2 or sarbecoviruses. They tested whether a surge in in vitro SARS-CoV-2 neutralization by the MB translated to higher in vivo protection at low doses.

They also assessed whether MBs could regain neutralization potency against all VOCs and extend their neutralization breadth to cover other CoVs, including sarbecoviruses.

For in vivo assessments against SARS-CoV-2 wild-type (WT) and Alpha, Beta, Gamma, Delta, and Omicron BA.1 VOCs, the team generated a self-assembled, oligomeric molecule capable of ultrapotent neutralization termed tri-specific 298-52-80 MB with antibody-like biochemical properties.

It had Fabs derived from three previously-identified mAbs of modest potency, mAbs 298, 52, and 80, which increased its neutralization potency by nearly 1,000-fold relative to the corresponding immunoglobulin G (IgG) cocktail, IgG4*.

The corresponding IgG cocktail with an IgG4 fragment, crystallizable (Fc) had five mutations, viz., S228P, F234A, L235A, G237A, and P238S, to abrogate binding to Fc-gamma receptors (FcγRs).

The researchers used cryogenic electron microscopy (cryo-EM) to confirm the proper assembly of this MB. Further, they determined molecular details of Fab interactions with the receptor-binding domain (RBD) by x-ray crystallography and antibody binding by biolayer interferometry (BLI). 

Results

The tri-specific 298-52-80 MB was nearly 1,000-fold more potent than the IgG4* antibody cocktail and exhibited a half-maximal inhibitory concentration (IC50) value of 0.0002 μg/ml.

Consistent with previous reports, substituting the Fc subtype from IgG1 to IgG4* did not affect the neutralization potency of the IgG or the MB.

Cryo-EM analysis of the tri-specific 298-52-80 MB showed minimal impact for single chain (sc)Fab and scFc genetic fusions. Nonetheless, the MB built on the apoferritin split design scaffold adopted its intended structural disposition, thus, substantiating the MB as a uniform biologic.

In vivo, MB displayed higher neutralization potency against the lethal SARS-CoV-2 challenge than the IgG4* cocktail at 430 times less molar amount than the IgG.

At an IC50 of 5 μg/ml, five mAbs, 52, 80, 2-36, 11-11, and 10-40, showed 100% neutralization breadth. After reducing the IC50 cutoff value to 0.01 μg/ml to resemble the potency of REGEN-COV, only two mAbs, 11-11 and 10-40, showed neutralizing activity against two SARS-CoV-2 VOCs.

Conversely, as mono-specific MBs, mAbs, 2-7, 80, and 52 reached 100% breadth at an IC50 cutoff value of 0.01 μg/ml. The remaining MBs lost potency against Omicron BA.1 but, except 298 and 2-38, still neutralized with an IC50 <0.3 μg/ml.

The spike (S) protein density on the virion surface might be favoring the increased avidity of the MB. Thus, while mAbs 80 and 2-7 lost potency against VOCs with mutations in the RBD, those mutations hardly altered the apparent binding affinity and neutralization profiles of these antibody molecules when displayed as MBs.

For human immunodeficiency virus 1 (HIV-1) and influenza, many years of research helped discover potent broadly-neutralizing antibody therapeutics.

On the contrary, the tri-specific MB incorporating the specificities 2-7, 10-40, and 11-11 showed potent in vitro neutralization across all SARS-CoV-2 VOCs, including recently emerged Omicron subvariants, BQ.1.1 and XBB.1.

More importantly, it expanded its neutralization breadth to other CoVs at neutralization potencies within the range of FDA-authorized SARS-CoV-2 therapeutics.

The potential of MB to tolerate viral sequence variability could be beneficial for antibody discovery timelines. It could help boost the endurance of previously-identified mAbs with the ability to neutralize emerging SARS-CoV-2 VOCs without marked increases in self-reactivity.

Due to a lack of multi-specificity, mono-specific 80 MB lost neutralization potency against the Omicron BA.5 VOC. Thus, combining multiple best-in-class antibodies into a multi-specific MB could help (re)gain more resilient neutralization potency amid rapid SARS-CoV-2 evolution. 

Moreover, combining multiple specificities into a single molecule shall ensure the bioavailability of all components throughout therapy, which, in the past, limited the effectiveness of mAb cocktails.

The larger footprint of the RBD covered by a tri-specific MB compared with conventional mAbs provides a unique advantage for the MBs in remaining resilient against future VOCs compared with mAbs alone.

However, continuous monitoring and screening of emerging variants will be required to confirm the persistence of neutralization.

Conclusions

To summarize, the study data presented 'proof of concept' that the MB platform harnessed avidity to increase the in vitro and in vivo potency and breadth of antibody-based therapeutics against SARS-CoV-2 and other coronaviruses.

The use of avidity-based increases in neutralization potency also facilitated the dose-sparing of mAb-based therapeutics.

Gains in neutralization potency in vivo were sufficient to confer protection from a lethal challenge even without effector functions.

Thus, future studies should investigate whether MB potency could be further enhanced via effector functions, achieved through the incorporation of wildtype or engineered Fc to introduce specific functionality.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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