Analysis of preclinical and clinical samples after treatment with a <scp>CD37</scp> targeting antibody drug conjugate (<scp>AGS67E</scp>) support a high level of <scp>CD37</scp> expression in <scp>NHL</scp>
Bibliographic record
Abstract
Introduction: AGS67E is an antibody drug conjugate against CD37 bound to monomethyl auristatin E (MMAE) via a protease-cleavable linker currently being investigated in subjects with relapsed/refractory NHL in a phase I dose-escalation study. CD37 is expressed in normal white blood cells (WBCs: B and T lymphocytes, NK cells, monocytes, and neutrophils). CD37 is also highly expressed in CLL, AML, and NHL, including 80% expression in DLBCL, as detected in tumor microarrays (TMA) of formalin-fixed paraffin-embedded (FFPE) tumor samples using the proprietary vCD37-9a73.1 antibody (Pereira et al., 2015). In contrast, the percentage of CD37 expression in DLBCL was recently determined to be 40% using a commercial antibody (2B8) on FFPE samples (Xu-Monette et al., 2016). Clinical and preclinical results, including a comparison of vCD37-9a73.1 with commercially available anti-CD37 reagents, are presented here in order to clarify the CD37 expression in DLBCL and in NHL in general. Methods: CD37 expression was investigated on WBCs by flow cytometry and on archived FFPE tumor samples by immunohistochemistry (IHC) from subjects in the phase I trial using the proprietary anti-CD37 antibody (vCD37-9a73.1). This antibody was selected for flow cytometry since it could detect CD37 on the surface of cells in the presence of AGS67E and showed similar CD37 levels to other anti-CD37 proprietary antibodies tested. The vCD37-9a73.1 and 2B8 antibodies were evaluated by IHC in FFPE cells and xenografts with different levels of CD37 mRNA levels, as well as in TMA of NHL. Results: CD37 expression in patient's WBCs was downregulated after AGS67E dosing, presumably due to AGS67E-mediated, dose-dependent decreases in WBCs. Furthermore, samples were CD37 positive as detected by both AGS67E and vCD37-9a73.1. These data support vCD37-9a73.1 as a suitable reagent for CD37 detection. IHC data from FFPE tumor samples from subjects enrolled in the ongoing phase I clinical trial with a variety of NHL pathologies demonstrated that CD37 was expressed in 100% of the samples examined (23 subjects) with an average H-score of 270 (maximum is 300), including 7 subjects with DLBCL (average H-score 277). Overall, the level and degree of expression were slightly higher than previously seen in TMA samples of NHL (~80%) with the same antibody and significantly higher than those reported with the 2B8 antibody. Evaluation of CD37 expression using vCD37-9a73.1 side-by-side with 2B8 in FFPE cells, xenografts, and TMA of NHL indicated that vCD37-9a73.1 has better sensitivity and specificity compared to 2B8 under the conditions tested. Keywords: CD37; diffuse large B-cell lymphoma (DLBCL); non-Hodgkin lymphoma (NHL)
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.020 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.007 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.003 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".