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>
Notice bibliographique
Résumé
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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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,005 | 0,020 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,007 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,003 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,002 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».