Bispecific 10E8.4/iMab broadly neutralizing antibody in people with or without HIV-1: a partially randomized phase 1 trial.
Theodore DA, Mayer BT, Rolle CP, DeJesus E, Ackerman ME, Seaman MS, Weiner JA, Mohri H, Huang Y, Gray B, Chang J, Gerber MW, Yu J, Luo Y, Padte NN, Yin MT, Barin B, Greene R, Palmer S, Pazmino A, Benitez J, Dorr C, McNairy M, DiRenzo J, Orzell CV, Ho DD, Hyrien O, Sobieszczyk ME
- DOI
- 10.1038/s41591-026-04472-w
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-22
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/a1867e4d-b55e-4755-850f-acced2587a3d is authoritative.
How this rating was calculated
- IntegrityIntegrity concern−0.5★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- ReportingStudy design partially met−0.25★
- CitationsUnresolved reference−0.25★
- LinksDead data/code link−0.25★
- No reported statistical tests were found to recompute.
- 01Efficacy rests on an unvalidated surrogate endpoint
The efficacy claim is based on reduction in plasma HIV-1 RNA (viral load) in viremic participants, which is a surrogate marker for clinical benefit. The paper does not provide evidence linking this surrogate to a hard clinical outcome, nor does it demonstrate target engagement at the tested dose beyond CD4 receptor occupancy, which is a pharmacodynamic marker but not a validated surrogate for clinical outcome.
“Each participant’s VL fell sharply following 10E8.4/iMab administration and rebounded as the antibody concentration and CD4RO decreased to low levels. Nadir VL was observed on day 14 for all three participants, reaching similar levels (209–389 copies ml−1).…”
- 02Treatment effect not shown to be clinically meaningful
The reported effect is a reduction in viral load of 1.68–1.97 logs in only three participants. This is not anchored to a minimal clinically important difference or a hard clinical outcome, and the small sample size and lack of comparator limit meaningfulness.
“The estimated participant-specific VL overall reduction ranged between 1.68 and 1.97 logs.”
- 03Declared data/code link does not resolve
Dead link — nothing to verify.
“https://github.com/FredHutch/Sim10e8imab”
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted and transparently reported phase 1 trial of a bispecific bnAb, with strong scientific premise, ethical approvals, data/code sharing, and reporting transparency. The main weakness is incomplete reporting of study design elements (randomization method, blinding, power analysis), which is typical for phase 1 but should be documented. Minor copyedit issues and a potential internal inconsistency in Table 2 warrant attention.
Both reviewers classified the study as interventional; no divergence. The statistics verification component found no recomputable tests (total=0), so statistical correctness was not machine-verified; only descriptive statistics and PK/PD modeling were assessed. The citation check flagged one reference not found in registry (Monolix Documentation), which is a potential fabrication signal. The integrity check flagged a potential internal contradiction in Table 2 regarding group sizes.
Numerical inconsistencies
1 finding · worst lowValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Internal contradictions in the reported numbersAssessed
- lowinternal contradictionIn Table 2, the column headers for arm 4 are 'Group J' and 'Group K' with n=6 each, but the text says 'In arm 4, PLWoH were randomized to receive 10E8.4/iMab or placebo 2.5 mg kg −1 SC or 10 mg kg −1 SC ( n = 9 each).' This suggests 9 per group, but the table shows 6 per group. However, the table also has a 'Placebo SC' column with n=6, so the total is 18, which matches the text. The discrepancy is that the text says 'n=9 each' for the two active groups, but the table shows n=6 for each active group and n=6 for placebo. This is a potential inconsistency.
“In arm 4, PLWoH were randomized to receive 10E8.4/iMab or placebo 2.5 mg kg −1 SC or 10 mg kg −1 SC ( n = 9 each).”
Table 2Find in source
Overstated conclusions
3 findings · worst highConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
6 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 210E8.4/iMab showed antiviral activity in viremic PLWH.The paper shows a decline in viral load in three participants, but the sample size is very small and the authors acknowledge the preliminary nature.Evidence: Results section reports viral load decline in group H participants, with nadir on day 14 and 1.68-1.97 log reduction.
“Each participant’s VL fell sharply following 10E8.4/iMab administration and rebounded as the antibody concentration and CD4RO decreased to low levels.”
ResultsFind in source - supportedReviewers 1, 210E8.4/iMab was safe and well tolerated across dose levels and administration routes.The paper reports no treatment-related serious AEs or AEs ≥ grade 3, and the primary safety objective was met.Evidence: Results section reports no serious AEs, no grade 3 or higher related AEs, and the primary outcome was met.
“No treatment-related serious adverse events (AEs) or AEs ≥ grade 3 were reported.”
AbstractFind in source - supportedReviewers 1, 2The PK/PD model can inform future trial design.The paper presents a detailed PK/PD model and a simulation tool, which is a reasonable basis for informing future trials.Evidence: The paper describes the model and provides a link to a simulation tool.
“Here, we developed a novel PK/PD model and corresponding tool that can inform future dosing ( https://pk10e8imab.fredhutch.org/ ) and trial design for combination studies of 10E8.4/iMab and other bnAbs.”
DiscussionFind in source - supportedReviewer 1The high ADA response rate suggests high immunogenicity of the molecule.The paper reports that 63% of participants developed ADAs, which is higher than frequently observed with other HIV antibodies.Evidence: Results section reports ADA detection in 25/39 PLWoH and 5/7 PLWH.
Treatment-induced or boosted ADA responses were observed in 25/39 (64%) PLWoH and 5/7 (71%) PLWH.
Resultsreviewer’s wording - supportedReviewer 2The high ADA response rate suggests high immunogenicity of 10E8.4/iMab.The paper reports ADA in 64% of PLWoH and 71% of PLWH, with functional inhibition in a subset, supporting the claim.Evidence: Results, ADAs section reports ADA rates and functional inhibition.
“Treatment-induced or boosted ADA responses were observed in 25/39 (64%) PLWoH and 5/7 (71%) PLWH”
ResultsFind in source - supportedReviewer 2These data support further study of 10E8.4/iMab to expand HIV treatment and prevention options.The safety and tolerability data, along with preliminary antiviral activity, provide a rationale for further studies, as stated in the Discussion.Evidence: The paper concludes with this recommendation based on the presented results.
“These data support further study of 10E8.4/iMab to expand HIV treatment and prevention options.”
AbstractFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe efficacy claim is based on reduction in plasma HIV-1 RNA (viral load) in viremic participants, which is a surrogate marker for clinical benefit. The paper does not provide evidence linking this surrogate to a hard clinical outcome, nor does it demonstrate target engagement at the tested dose beyond CD4 receptor occupancy, which is a pharmacodynamic marker but not a validated surrogate for clinical outcome.
“Each participant’s VL fell sharply following 10E8.4/iMab administration and rebounded as the antibody concentration and CD4RO decreased to low levels. Nadir VL was observed on day 14 for all three participants, reaching similar levels (209–389 copies ml−1). The estimated participant-specific VL overall reduction ranged between 1.68 and 1.97 logs.”
- INADEQUATEEffect sizeThe reported effect is a reduction in viral load of 1.68–1.97 logs in only three participants. This is not anchored to a minimal clinically important difference or a hard clinical outcome, and the small sample size and lack of comparator limit meaningfulness.
“The estimated participant-specific VL overall reduction ranged between 1.68 and 1.97 logs.”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Study-design details incomplete (controls, blinding, power)Assessed
The introduction cites extensive prior research on bnAbs, bispecific antibodies, and the specific 10E8.4/iMab antibody, including its potency and breadth. The rationale for the study is clearly linked to the need for long-acting HIV prevention and treatment options. The paper acknowledges limitations of prior work, such as the need for combination therapy and the challenges of immunogenicity, and addresses them in the study design.
The trial is described as 'partially randomized' with only arm 4 being randomized to active or placebo. The randomization method is not specified (e.g., computer-generated, block). Blinding is not mentioned; it is likely open-label for the non-randomized arms, but this is not explicitly stated. No a priori power analysis is reported, which is common for phase 1 trials but still a limitation. Inclusion/exclusion criteria are described in detail. Outlier handling is not explicitly described, but the analysis population (safety population) is defined. Controls are present (placebo in arm 4). Independent replication is not applicable for a single phase 1 trial.
“In arm 4, PLWoH were randomized to receive 10E8.4/iMab or placebo 2.5 mg kg −1 SC or 10 mg kg −1 SC ( n = 9 each).”
“Eligible participants were 18–60 years of age and in good health.”
The paper reports sex at birth, gender, age, weight, ethnicity, and race in Table 1. It also reports HIV status and relevant clinical characteristics such as CD4 count and viral load. Since this is a human trial, species/strain and housing conditions are not applicable. Sex is reported for all participants, and the paper notes that no female PLWH were enrolled, which is a limitation discussed.
“Although the trial reached its goal of enrolling at least approximately 40% of each sex overall, there were no female PLWH.”
“Median age was 27.5 years, and 26 (48.1%) were assigned female at birth.”
“Although the trial reached its goal of enrolling at least approximately 40% of each sex overall, there were no female PLWH.”
The paper states that the study was approved by the Institutional Review Board of Columbia University Irving Medical Center (IRB AAAS1239) and the Advarra Institutional Review Board (IRB PRo00037972). All participants provided written informed consent. The study complied with relevant ethical regulations. This is a human trial, so IACUC is not applicable.
“The study and all amendments and protocol deviations were approved by the Institutional Review Board of Columbia University Irving Medical Center (CUIMC; IRB AAAS1239) and the Advarra Institutional Review Board (IRB PRo00037972).”
“All participants provided written informed consent.”
“The study and all amendments and protocol deviations were approved by the Institutional Review Board of Columbia University Irving Medical Center (CUIMC; IRB AAAS1239) and the Advarra Institutional Review Board (IRB PRo00037972).”
“All participants provided written informed consent.”
“This study complied with all relevant ethical regulations.”
The investigational product is a bispecific antibody, and the paper describes its components (10E8.4 and iMab arms) and engineering (enhanced half-life, reduced Fc-effector functions). The source of the antibody is not explicitly stated, but it is a clinical trial product. The PK/PD modeling software (R, nls function) is identified. Other bench reagents are not applicable as this is a clinical trial.
“Models were fit via non-linear least squares using the Golub-Pereyra algorithm implemented in R (nls function).”
“10E8.4/iMab was administered intravenously (IV) or subcutaneously (SC).”
“Models were fit via non-linear least squares using the Golub-Pereyra algorithm implemented in R (nls function).”
The paper primarily reports descriptive statistics (frequencies, percentages, medians) and PK/PD model estimates with confidence intervals. No hypothesis tests are reported for the primary outcome; instead, safety is described. The PK/PD model is described in detail, and model parameters are reported with relative standard errors. The paper does not report p-values for the main analyses, which is acceptable for a phase 1 trial. The statistical software (R) is identified. Data presentation includes tables with n and percentages, and figures with error bars.
“Values are reported as n (%) (95% CI).”
The data availability statement specifies that the full analyzable dataset will be available through the Vivli platform with a DOI (10.25934/PR00012686). This is a concrete managed-access route, which is adequate for patient-level data. Code is shared in two GitHub repositories, which is reported_and_adequate. Repository deposit and accession numbers are not applicable for patient-level data.
“The full analyzable data set (all participant-level data collected in the study, including safety and immunogenicity data) and all versions of the protocol used in the trial will be available indefinitely through the Vivli platform at 10.25934/PR00012686.”
“The full analyzable data set (all participant-level data collected in the study, including safety and immunogenicity data) and all versions of the protocol used in the trial will be available indefinitely through the Vivli platform at 10.25934/PR00012686.”
“All R code required to reproduce the results are available at https://github.com/HyrienLab/ABA0101Manuscript/ . The code supporting the shiny application is available at https://github.com/FredHutch/Sim10e8imab .”
The trial is registered at ClinicalTrials.gov (NCT03875209). A CONSORT checklist is mentioned in the supplementary information. All outcomes are reported, including negative findings (e.g., no serious AEs). Limitations are discussed in detail. Conclusions are proportional, acknowledging the small sample size and preliminary nature of antiviral findings. Funding and competing interests are declared.
“Supplementary Information Supplementary Figures 1–6, Supplementary Tables 1–4, CONSORT checklist.”
“This study has limitations. As described above, denser ADA sampling could have supported analysis of potential ADA impact on PK.”
“ClinicalTrials.gov: NCT03875209 (https://clinicaltrials.gov/study/NCT03875209) .”
“Supplementary Figures 1–6, Supplementary Tables 1–4, CONSORT checklist.”
“This study has limitations. As described above, denser ADA sampling could have supported analysis of potential ADA impact on PK.”
Registered (2 IDs: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
2 findings · worst mediumReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
- Dead data/code linksRecomputed
- References not resolvable to a published paperRecomputed
Checked 57 references by DOI: 50 verified — 1 DOI unresolved, 6 no DOI (shown, not verified).
- UNRESOLVED10.5281/zenodo.14918014Monolix Documentation (2024R1)Cited DOI does not resolve to any Crossref record.
- NO DOIGlobal HIV & AIDS statistics — fact sheetNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIIbalizumab, a CD4-specific mAb to inhibit HIV-1 infectionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIClinical pharmacology and biopharmaceutics review(s): BLA 761065, ibalizumab (Trogarzo)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIA 24-week phase II maintenance study of TMB-365/TMB-380 Q8W in people with suppressed HIV-1 infectionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIR: A Language and Environment for Statistical ComputingNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOItidyverse: easily install and load the ‘Tidyverse’No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
5 data/code links checked; 4 live, 1 dead.
- datahttps://clinicaltrials.gov/study/NCT03875209LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT05890963LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://pk10e8imab.fredhutch.org/LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- codeGitHubLIVEHTTP 200https://github.com/HyrienLab/ABA0101Manuscript/Resolves to GitHub (code repository).
- codeGitHubDEADHTTP 404https://github.com/FredHutch/Sim10e8imabDead link — nothing to verify.
Copyediting
7 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 7 minor suggestions below.
7 copyedit issues flagged: mostly consistency, clarity, typo.
- MINORconsistencyAbstract“54 participants living with HIV (PLWH) or without HIV (PLWoH) received 10E8.4/iMab or placebo.”→ Consider specifying the number of participants who received placebo vs. active.The abstract states 54 participants received drug or placebo, but the breakdown is not given.
- MINORclarityResults, Trial design and participant disposition“There were eight protocol amendments (described in ).”→ Provide a reference to the supplementary material or a table listing the amendments.The reference is missing.
- MINORtypoResults, PK in PLWoH“CDR4O data were analyzed as measured”→ Change to 'CD4RO data were analyzed as measured'.Typographical error: CDR4O should be CD4RO.
- MINORconsistencyTable 2“Group J | Group K | Groups J-K”→ Ensure column headers are consistent with the text (e.g., 'Placebo' column).The table has a combined column for groups J-K, but the text refers to them separately.
- MINORtypoResults, PK in PLWoH“CDR4O data were analyzed as measured”→ CD4RO data were analyzed as measuredTypo in 'CDR4O' should be 'CD4RO'.
- MINORconsistencyAbstract“54 participants living with HIV (PLWH) or without HIV (PLWoH) received 10E8.4/iMab or placebo.”→ Consider clarifying that 54 participants received the product or placebo, but the total enrolled was 54.The abstract states 54 received, but the results say 54 enrolled and received; consistent.
- MINORclarityResults, Trial design and participant disposition“There were eight protocol amendments (described in ).”→ Provide a reference to the supplementary material or protocol for the amendments.The reference is missing in the text.
The published work is robust overall, but readers should weigh the incomplete reporting of randomization and blinding, the lack of a power analysis, and the potential internal inconsistency in Table 2. An erratum or clarification may be warranted for the Table 2 discrepancy and the missing reference. The paper is otherwise well-reported and transparent.
- 1.HIGHrigorResolve the internal contradiction in Table 2: the text states arm 4 had n=9 per active group, but the table shows n=6 per active group and n=6 for placebo. Clarify the correct group sizes and ensure consistency between text and table.An internal contradiction in reported participant numbers is a validity threat that could mislead readers and may warrant an erratum.
- 2.HIGHreportingIn the Methods section, explicitly describe the randomization method used in arm 4 (e.g., computer-generated sequence, block size, allocation concealment).The randomization method is not reported, which is a key design element for a randomized arm.
- 3.HIGHreportingIn the Methods section, state whether the trial was open-label or blinded, and if blinded, describe the blinding of participants, investigators, and outcome assessors.Blinding is not mentioned, and this is a standard reporting requirement for clinical trials.
- 4.HIGHreportingIn the Methods section, provide a sample size justification or rationale for not performing a formal power analysis.No power analysis is reported, and a justification would strengthen the study design section.
- 5.HIGHreportingIn the Methods section, describe how outliers or protocol deviations were handled in the statistical analysis, particularly for the PK/PD modeling.Outlier handling is not explicitly described, which is a reporting gap.
- 6.HIGHdata codeFix the dead link in the code availability: verify that the GitHub repository https://github.com/HyrienLab/ABA0101Manuscript/ is accessible and contains the stated code.A dead link undermines the data/code availability statement and reproducibility.
- 7.HIGHotherVerify or correct the reference 'Monolix Documentation (2024R1)' (DOI 10.5281/zenodo.14918014) which was not found in any registry; if it is a software manual, provide a proper citation or link.A reference that cannot be found in any registry may be fabricated or incorrectly cited.
- 8.MEDIUMcopyeditFix the typo 'CDR4O' to 'CD4RO' in the Results section (PK in PLWoH).Typographical error in a key biomarker name could confuse readers.
- 9.MEDIUMcopyeditProvide a reference for the eight protocol amendments in the Results section (currently 'described in ' with a missing reference).Missing reference for protocol amendments reduces transparency.
- 10.MEDIUMcopyeditClarify the abstract statement about the number of participants receiving active vs. placebo.The abstract states 54 participants received drug or placebo, but the breakdown is not given; clarity would help readers.
- 11.MEDIUMreportingIn the Discussion, expand on the implications of the lack of female PLWH and how future trials will address this.The lack of female PLWH is a limitation that could affect generalizability.
- 12.MEDIUMreportingIn the Data Availability section, clarify the conditions for accessing the data via Vivli (e.g., proposal review, timeline).Clarifying access conditions improves transparency for potential data reusers.
- 13.LOWreportingConsider reporting exact p-values for any exploratory comparisons, or explicitly state that no inferential statistics were performed.This would improve statistical reporting clarity.
- 14.LOWreportingAdd a statement on the manufacturer and lot number of the investigational product in the Methods section.Enhances resource identification for the investigational product.
- 15.LOWreportingClarify the role of the Safety Monitoring Committee and any interim analyses in the Methods section.Provides additional context on trial oversight.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.