Efficacy of ormutivimab, a novel recombinant human anti-rabies monoclonal antibody, in post-exposure prophylaxis animal models

Zhai, Lili; Wang, Hui; Zhao, Wei; Zhang, Shoufeng; Miao, Faming; Cao, Yang; Chen, Chen; Li, Yufeng; Gao, Jie; Lv, Ruo-yun; Zhang, Shixiong; Cao, Jia-bin; Zhang, Xu-fan; Yang, Mingming; Zhang, Bin; Zhao, Jing; Wei, Jingshuang; Gao, Jian

doi:10.1016/j.tmaid.2022.102267

Cited by 14 publications

(9 citation statements)

References 29 publications

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Section: Discussionmentioning

confidence: 99%

“…Due to the global shortage and high price of HRIG, WHO recommended the use of mAbs as alternatives for RIG in PEP, and to date, several mAbs have been approved or are in clinical trials. [43][44][45] As an integral part of PEP where vaccination usually takes time to induce an immune response, passive immunization of anti-RABV mAbs could neutralize RABV and lyse infected cells by ADCC immediately after RABV exposure. Another advantage of mAbs is that these could be optimized and engineered to a specific purpose; for example, ADCC activity could be enhanced by optimal mutations of amino acids in the Fc region or optimization of Fc glycosylation by glycoengineering.…”

Section: Discussionmentioning

confidence: 99%

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Development of a reporter gene assay for antibody dependent cellular cytotoxicity activity determination of anti‐rabies virus glycoprotein antibodies

Wang

Cui

et al. 2022

Microbiology and Immunology

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Rabies is a viral disease that is nearly 100% fatal once clinical signs and symptoms develop. Post-exposure prophylaxis can efficiently prevent rabies, and antibody (Ab) induction by vaccination or passive immunization of human rabies immunoglobulin (HRIG) or monoclonal antibodies (mAbs) play an integral role in prevention against rabies. In addition to their capacity to neutralize viruses, antibodies exert their antiviral effects by antibody-dependent cellular cytotoxicity (ADCC), which plays an important role in antiviral immunity and clearance of viral infections. For antibodies against rabies virus (RABV), evaluation of ADCC activity was neglected. Here, we developed a robust cell-based reporter gene assay (RGA) for the determination of the ADCC activity of anti-RABV antibodies using CVS-N2c-293 cells, which stably express the glycoprotein (G) of RABV strain CVS-N2c as target cells, and Jurkat cells, which stably express FcγRⅢa and nuclear factor of activated T cells (NFAT) reporter gene as effector cells (Jurkat/NFAT-luc/FcγRⅢa cells). The experimental parameters were carefully optimized, and the established ADCC assay was systematically validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q2 guideline. We also evaluated the ADCC activity of anti-RABV antibodies, including mAbs, HRIG, and vaccine induced antisera, and found that all test antibodies exhibited ADCC activity with varied strengths. The established RGA provides a novel method for evaluating the ADCC of anti-RABV antibodies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Development of a reporter gene assay for antibody dependent cellular cytotoxicity activity determination of anti‐rabies virus glycoprotein antibodies

Wang

Cui

et al. 2022

Microbiology and Immunology

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“…Due to the high cost and supply shortages of RIGs, the WHO recommends since the 1990’s the development of alternatives [23]. Some monoclonals have been licensed for respectively the Indian (Rabishield and Twinrab) [24] and Chinese (Ormutivimab) market, but suffer obviously from the same shortcomings [5].…”

Section: Discussionmentioning

confidence: 99%

“…However, RIGs are scarce in endemic regions [3,4] due to their short shelf-life, the need for a cold chain and the high cost of manufacturing. It is estimated that less than 2% of severely exposed patients (category III) receive RIGs worldwide [5,6].…”

Section: Introductionmentioning

confidence: 99%

TheUrtica DioicaAgglutinin Prevents Rabies Virus Infection in a Muscle Explant Model

Wang

Terrie

et al. 2021

Preprint

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Infection with the rabies virus (RABV) causes fatal encephalitis and paralysis in humans and animals. Post-exposure prophylaxis (PEP) consists of vaccination and the injection of anti-rabies immunoglobulins (RIGs) around the (bite) wound. This is 100% effective in preventing disease if administered in a timely manner. However, the costs, the required cold chain for storage and transport and the limited availability of RIGs makes the treatment challenging. Cheaper and easier to produce alternatives are urgently needed. To aid in the discovery and development of such alternative therapeutics, we developed a physiological relevant infection model. Strips of freshly dissected swine skeletal muscle were placed under tension in culture medium and infected with RABV. Viral antigens were produced in the muscle explants and the virus production increased significantly over time, indicating that RABV infects and replicates in the muscle explants. Subsequently, in a search for inhibitors of RABV entry in muscle cells, we first screened a panel of 34 different lectins in a RABV / BHK-21J cell assay. The Urtica Dioica (stinging nettle) Agglutinin (UDA; a N-acetyl-D-glucosamine specific agglutinin) was found to be able to completely inhibit infection of cells with the RABV (EC50 8.2 μg/mL) by preventing binding of the virus to the host cell. When the infection of the muscle strips was carried out in the presence of UDA, infection of the tissue was completely prevented. We thus developed a physiological relevant RABV muscle infection model and identified an easy to produce component that (i) may serve as a reference for further studies and (ii) holds promise as an alternative for RIGs in PEP.

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“…In post-exposure prophylaxis animal models, ormutivimab was able to neutralize a broad panel of Chinese-prevalent street rabies viruses and had comparable protection to that achieved with polyclonal human rabies immunoglobulin (HRIG) up to a high dose level (200 IU/kg). 54 The effects of ormutivimab or HRIG administered with or without rabies vaccine in healthy adults were evaluated in a Phase 2 study (NCT02559921). The study enrolled 300 patients and had 3 arms in which patients received antibody only (ormutivimab (20 IU·kg−1), ormutivimab (40 IU·kg−1), or HRIG (20 IU·kg−1)), and 4 arms in which participants received antibody in combination with a purified Vero cell rabies vaccine (ormutivimab (20 IU·kg−1), ormutivimab (40 IU·kg−1), HRIG (20 IU·kg−1), or placebo.…”

Section: Antibody Therapeutics First Approved or Undergoing Regulator...mentioning

confidence: 99%

Antibodies to watch in 2023

Kaplon

Crescioli

Chenoweth

et al. 2022

mAbs

189

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In this 14th installment of the annual Antibodies to Watch article series, we discuss key events in commercial monoclonal antibody therapeutics development that occurred in 2022 and forecast events that might occur in 2023. As of mid-November, 12 antibody therapeutics had been granted first approvals in either the United States or European Union (tebentafusp (Kimmtrak), faricimab (Vabysmo), sutimlimab (Enjaymo), relatlimab (Opdualag), tixagevimab/cilgavimab (Evusheld), mosunetuzumab (Lunsumio), teclistamab (TECVAYLI), spesolimab (SPEVIGO), tremelimumab (Imjudo; combo with durvalumab), nirsevimab (Beyfortus), mirvetuximab soravtansine (ELAHERE™), and teplizumab (TZIELD)), including 4 bispecific antibodies and 1 ADC. Based on FDA action dates, several additional product candidates could be approved by the end of 2022. An additional seven were first approved in China or Japan in 2022, including two bispecific antibodies (cadonilimab and ozoralizumab). Globally, at least 24 investigational antibody therapeutics are undergoing review by regulatory agencies as of mid-November 2022. Our data show that, with antibodies for COVID-19 excluded, the late-stage commercial clinical pipeline grew by ~20% in the past year to include nearly 140 investigational antibody therapeutics that were designed using a wide variety of formats and engineering techniques. Of those in late-stage development, marketing application submissions for at least 23 may occur by the end of 2023, of which 5 are bispecific (odronextamab, erfonrilimab, linvoseltamab, zanidatamab, and talquetamab) and 2 are ADCs (datopotamab deruxtecan, and tusamitamab ravtansine).

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Efficacy of ormutivimab, a novel recombinant human anti-rabies monoclonal antibody, in post-exposure prophylaxis animal models

Cited by 14 publications

References 29 publications

Development of a reporter gene assay for antibody dependent cellular cytotoxicity activity determination of anti‐rabies virus glycoprotein antibodies

Development of a reporter gene assay for antibody dependent cellular cytotoxicity activity determination of anti‐rabies virus glycoprotein antibodies

TheUrtica DioicaAgglutinin Prevents Rabies Virus Infection in a Muscle Explant Model

Antibodies to watch in 2023

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