Randomized, placebo-controlled, single-blind phase 1 studies of the safety, tolerability, and pharmacokinetics of BRII-196 and BRII-198, SARS-CoV-2 spike-targeting monoclonal antibodies with an extended half-life in healthy adults
Xiaohua Hao, Zheng Zhang, Ji Ma, Lin Cheng, Yun Ji, Yang Liu, Dong Zhao, Wen Zhang, Chunming Li, Li Yan, David Margolis, Qing Zhu, Yao Zhang, Fujie Zhang
Frontiers in Pharmacology, doi:10.3389/fphar.2022.983505
Background: are two anti-SARS-CoV-2 monoclonal neutralizing antibodies as a cocktail therapy for treating COVID-19 with a modified Fc region that extends half-life. Methods: Safety, tolerability, pharmacokinetics, and immunogenicity of were investigated in first-in-human, placebo-controlled, single ascending dose phase 1 studies in healthy adults. 44 participants received a single intravenous infusion of single BRII-196 or BRII-198 up to 3,000 mg, or combination up to 1500/1500 mg, or placebo and were followed up for 180 days. Primary endpoints were incidence of adverse events (AEs) and changes from pre-dose baseline in clinical assessments. Secondary endpoints included pharmacokinetics profiles of and detection of anti-drug antibodies (ADAs). Plasma neutralization activities against SARS-CoV-2 Delta live virus in comparison to post-vaccination plasma were evaluated as exploratory endpoints. Results: All infusions were well-tolerated without systemic or local infusion reactions, dose-limiting AEs, serious AEs, or deaths. Most treatment-emergent AEs were isolated asymptomatic laboratory abnormalities of grade 1-2 in
Placebo (n = 4) Participants with any TEAE 3 (100%) 5 (83%) 2 (67%) 4 (100%) Participants with Grade 1 TEAE 3 (100%) 5 (83%) 2 (67%) 4 (100%) Participants with Grade 2 TEAE 1 (33%) 3 (50%) 0 2 (50%) Gastrointestinal disorders 1 (33%) 1 (17%) 0 0 Injury, poisoning, and procedural complications 0 0 0 1 (25%) Abbreviations: TEAE, treatment-emergent adverse event; SOC, system organ class. Participants who experienced the same AE on more than one occasion (based on the specific category) are counted once in each relevant category. Percentages are based on the number of participants in the treatment group. a 1 participant had an elevated blood creatine phosphokinase of Grade 4 after excessive exercise, and 1 participant had increased blood triglycerides of Grade 3 on day 181. Both events were not considered as related to the study drug by the investigators and normalized within 1-3 weeks. b 1 participant receiving placebo had a serious TEAE (bilateral traumatic foot fracture leading to hospitalization, which was also reported as a Grade 3 TEAE). The participant recovered after surgery. c Only SOCs experienced by ≥ 2 participant or with the maximum severity category ≥ Grade 2 are included.
Ethics statement The studies involving human participants were reviewed and approved by Beijing Ditan Hospital, Capital Medical University, Beijing, China. The patients/participants provided their written informed consent to participate in this study.
Author contributions XH, WZ, DZ, YL and..
References
Chen, Nirula, Heller, Gottlieb, Boscia et al., SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2029849Evering, Giganti, Chew, Hughes, Moser et al., LB2. Safety and efficacy of combination SARS-CoV-2 monoclonal neutralizing antibodies (mAb) BRII-196 and BRII-198 in non-hospitalized COVID-19 patients, Open Forum Infect. Dis,
doi:10.1093/ofid/ofab466.1643Jin, Lei, Hu, Dimitrov, Ying, Human monoclonal antibodies as candidate therapeutics against emerging viruses, Front. Med,
doi:10.1007/s11684-017-0596-6Khoury, Cromer, Reynaldi, Schlub, Wheatley et al., Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection, Nat. Med,
doi:10.1038/s41591-021-01377-8Robbie, Criste, Dall'acqua, Jensen, Patel et al., A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults, Antimicrob. Agents Chemother,
doi:10.1128/AAC.01285-13Saunders, Conceptual approaches to modulating antibody effector functions and circulation half-life, Front. Immunol,
doi:10.3389/fimmu.2019.01296Self, Sandkovsky, Reilly, Vock, Gottlieb et al., Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): A randomised controlled trial, Lancet Infect. Dis,
doi:10.1016/S1473-3099(21)00751-9Wang, Guo, Iketani, Li, Mohri et al., SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 subvariants evolved to extend antibody evasion,
doi:10.1101/2022.05.26.493517Wang, Zhang, Ge, Ren, Zhang et al., Analysis of SARS-CoV-2 variant mutations reveals neutralization escape mechanisms and the ability to use ACE2 receptors from additional species, Immunity,
doi:10.1016/j.immuni.2021.06.003Weinreich, Sivapalasingam, Norton, Ali, Gao et al., REGN-COV2, a neutralizing antibody cocktail, in outpatients with covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2035002Zhou, Cheng, Song, Guo, Shen et al., Identification and application of a pair of noncompeting monoclonal antibodies broadly binding to the nucleocapsid proteins of SARS-CoV-2 variants including Omicron, Virol. J,
doi:10.1186/s12985-022-01827-w{ 'indexed': {'date-parts': [[2024, 5, 17]], 'date-time': '2024-05-17T07:12:39Z', 'timestamp': 1715929959342},
'reference-count': 14,
'publisher': 'Frontiers Media SA',
'license': [ { 'start': { 'date-parts': [[2022, 9, 6]],
'date-time': '2022-09-06T00:00:00Z',
'timestamp': 1662422400000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'content-domain': {'domain': ['frontiersin.org'], 'crossmark-restriction': True},
'abstract': '<jats:p><jats:bold>Background:</jats:bold> BRII-196 and BRII-198 are two anti-SARS-CoV-2 '
'monoclonal neutralizing antibodies as a cocktail therapy for treating COVID-19 with a '
'modified Fc region that extends half-life.</jats:p><jats:p><jats:bold>Methods:</jats:bold> '
'Safety, tolerability, pharmacokinetics, and immunogenicity of BRII-196 and BRII-198 were '
'investigated in first-in-human, placebo-controlled, single ascending dose phase 1 studies in '
'healthy adults. 44 participants received a single intravenous infusion of single BRII-196 or '
'BRII-198 up to 3,000\xa0mg, or BRII-196 and BRII-198 combination up to 1500/1500\xa0mg, or '
'placebo and were followed up for 180 days. Primary endpoints were incidence of adverse events '
'(AEs) and changes from pre-dose baseline in clinical assessments. Secondary endpoints '
'included pharmacokinetics profiles of BRII-196/BRII-198 and detection of anti-drug antibodies '
'(ADAs). Plasma neutralization activities against SARS-CoV-2 Delta live virus in comparison to '
'post-vaccination plasma were evaluated as exploratory '
'endpoints.</jats:p><jats:p><jats:bold>Results:</jats:bold> All infusions were well-tolerated '
'without systemic or local infusion reactions, dose-limiting AEs, serious AEs, or deaths. Most '
'treatment-emergent AEs were isolated asymptomatic laboratory abnormalities of grade 1-2 in '
'severity. BRII-196 and BRII-198 displayed pharmacokinetics characteristic of Fc-engineered '
'human IgG1 with mean terminal half-lives of 44.6–48.6\xa0days and 72.2–83.0\xa0days, '
'respectively, with no evidence of interaction or significant anti-drug antibody development. '
'Neutralizing activities against the live virus of the SARS-CoV-2 Delta variant were '
'maintained in plasma samples taken on day 180 '
'post-infusion.</jats:p><jats:p><jats:bold>Conclusion:</jats:bold> BRII-196 and BRII-198 are '
'safe, well-tolerated, and suitable therapeutic or prophylactic options for SARS-CoV-2 '
'infection.</jats:p><jats:p><jats:bold>Clinical Trial '
'Registration:</jats:bold><jats:ext-link>ClinicalTrials.gov</jats:ext-link> under identifiers '
'NCT04479631, NCT04479644, and NCT04691180.</jats:p>',
'DOI': '10.3389/fphar.2022.983505',
'type': 'journal-article',
'created': {'date-parts': [[2022, 9, 6]], 'date-time': '2022-09-06T10:16:40Z', 'timestamp': 1662459400000},
'update-policy': 'http://dx.doi.org/10.3389/crossmark-policy',
'source': 'Crossref',
'is-referenced-by-count': 4,
'title': 'Randomized, placebo-controlled, single-blind phase 1 studies of the safety, tolerability, and '
'pharmacokinetics of BRII-196 and BRII-198, SARS-CoV-2 spike-targeting monoclonal antibodies with '
'an extended half-life in healthy adults',
'prefix': '10.3389',
'volume': '13',
'author': [ {'given': 'Xiaohua', 'family': 'Hao', 'sequence': 'first', 'affiliation': []},
{'given': 'Zheng', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ji', 'family': 'Ma', 'sequence': 'additional', 'affiliation': []},
{'given': 'Lin', 'family': 'Cheng', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yun', 'family': 'Ji', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yang', 'family': 'Liu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Dong', 'family': 'Zhao', 'sequence': 'additional', 'affiliation': []},
{'given': 'Wen', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Chunming', 'family': 'Li', 'sequence': 'additional', 'affiliation': []},
{'given': 'Li', 'family': 'Yan', 'sequence': 'additional', 'affiliation': []},
{'given': 'David', 'family': 'Margolis', 'sequence': 'additional', 'affiliation': []},
{'given': 'Qing', 'family': 'Zhu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yao', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Fujie', 'family': 'Zhang', 'sequence': 'additional', 'affiliation': []}],
'member': '1965',
'published-online': {'date-parts': [[2022, 9, 6]]},
'reference': [ { 'key': 'B1',
'doi-asserted-by': 'publisher',
'first-page': '229',
'DOI': '10.1056/NEJMoa2029849',
'article-title': 'SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with covid-19',
'volume': '384',
'author': 'Chen',
'year': '2021',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': 'B2',
'doi-asserted-by': 'publisher',
'first-page': 'S807',
'DOI': '10.1093/ofid/ofab466.1643',
'article-title': 'LB2. Safety and efficacy of combination SARS-CoV-2 monoclonal '
'neutralizing antibodies (mAb) BRII-196 and BRII-198 in non-hospitalized '
'COVID-19 patients',
'volume': '8',
'author': 'Evering',
'year': '2021',
'journal-title': 'Open Forum Infect. Dis.'},
{ 'key': 'B3',
'doi-asserted-by': 'publisher',
'first-page': '2547',
'DOI': '10.1001/jama.2016.16477',
'article-title': 'Prevalence of immunosuppression among US adults, 2013',
'volume': '316',
'author': 'Harpaz',
'year': '2016',
'journal-title': 'JAMA'},
{ 'key': 'B4',
'doi-asserted-by': 'publisher',
'first-page': '462',
'DOI': '10.1007/s11684-017-0596-6',
'article-title': 'Human monoclonal antibodies as candidate therapeutics against emerging '
'viruses',
'volume': '11',
'author': 'Jin',
'year': '2017',
'journal-title': 'Front. Med.'},
{ 'key': 'B5',
'doi-asserted-by': 'publisher',
'first-page': '115',
'DOI': '10.1038/s41586-020-2380-z',
'article-title': 'Human neutralizing antibodies elicited by SARS-CoV-2 infection',
'volume': '584',
'author': 'Ju',
'year': '2020',
'journal-title': 'Nature'},
{ 'key': 'B6',
'doi-asserted-by': 'publisher',
'first-page': '1205',
'DOI': '10.1038/s41591-021-01377-8',
'article-title': 'Neutralizing antibody levels are highly predictive of immune protection '
'from symptomatic SARS-CoV-2 infection',
'volume': '27',
'author': 'Khoury',
'year': '2021',
'journal-title': 'Nat. Med.'},
{ 'key': 'B7',
'doi-asserted-by': 'publisher',
'first-page': '6147',
'DOI': '10.1128/AAC.01285-13',
'article-title': 'A novel investigational Fc-modified humanized monoclonal antibody, '
'motavizumab-YTE, has an extended half-life in healthy adults',
'volume': '57',
'author': 'Robbie',
'year': '2013',
'journal-title': 'Antimicrob. Agents Chemother.'},
{ 'key': 'B8',
'doi-asserted-by': 'publisher',
'first-page': '1296',
'DOI': '10.3389/fimmu.2019.01296',
'article-title': 'Conceptual approaches to modulating antibody effector functions and '
'circulation half-life',
'volume': '10',
'author': 'Saunders',
'year': '2019',
'journal-title': 'Front. Immunol.'},
{ 'key': 'B9',
'doi-asserted-by': 'publisher',
'first-page': '622',
'DOI': '10.1016/S1473-3099(21)00751-9',
'article-title': 'Efficacy and safety of two neutralising monoclonal antibody therapies, '
'sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with '
'COVID-19 (TICO): A randomised controlled trial',
'volume': '22',
'author': 'Self',
'year': '2022',
'journal-title': 'Lancet Infect. Dis.'},
{ 'key': 'B10',
'doi-asserted-by': 'publisher',
'first-page': '130',
'DOI': '10.1038/s41586-021-03398-2',
'article-title': 'Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7',
'volume': '593',
'author': 'Wang',
'year': '',
'journal-title': 'Nature'},
{ 'key': 'B11',
'volume-title': 'SARS-CoV-2 Omicron BA.2.12.1, BA.4, and BA.5 subvariants evolved to '
'extend antibody evasion',
'author': 'Wang',
'year': '2022'},
{ 'key': 'B12',
'doi-asserted-by': 'publisher',
'first-page': '1611',
'DOI': '10.1016/j.immuni.2021.06.003',
'article-title': 'Analysis of SARS-CoV-2 variant mutations reveals neutralization escape '
'mechanisms and the ability to use ACE2 receptors from additional '
'species',
'volume': '54',
'author': 'Wang',
'year': '',
'journal-title': 'Immunity'},
{ 'key': 'B13',
'doi-asserted-by': 'publisher',
'first-page': '238',
'DOI': '10.1056/NEJMoa2035002',
'article-title': 'REGN-COV2, a neutralizing antibody cocktail, in outpatients with '
'covid-19',
'volume': '384',
'author': 'Weinreich',
'year': '2021',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': 'B14',
'doi-asserted-by': 'publisher',
'first-page': '96',
'DOI': '10.1186/s12985-022-01827-w',
'article-title': 'Identification and application of a pair of noncompeting monoclonal '
'antibodies broadly binding to the nucleocapsid proteins of SARS-CoV-2 '
'variants including Omicron',
'volume': '19',
'author': 'Zhou',
'year': '2022',
'journal-title': 'Virol. J.'}],
'container-title': 'Frontiers in Pharmacology',
'original-title': [],
'link': [ { 'URL': 'https://www.frontiersin.org/articles/10.3389/fphar.2022.983505/full',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 9, 6]],
'date-time': '2022-09-06T10:16:44Z',
'timestamp': 1662459404000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.frontiersin.org/articles/10.3389/fphar.2022.983505/full'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2022, 9, 6]]},
'references-count': 14,
'alternative-id': ['10.3389/fphar.2022.983505'],
'URL': 'http://dx.doi.org/10.3389/fphar.2022.983505',
'relation': { 'has-preprint': [ { 'id-type': 'doi',
'id': '10.1101/2021.07.21.21260964',
'asserted-by': 'object'}]},
'ISSN': ['1663-9812'],
'subject': [],
'container-title-short': 'Front. Pharmacol.',
'published': {'date-parts': [[2022, 9, 6]]}}
