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Preprint WatchModerateOctober 19th, 2026

A Multiplex Protein Microarray Platform for Preclinical Tissue Binding and Cross-Reactivity of Therapeutic Antibodies

Matsukura, S.; Sawada, N.; Watanabe, M.; Tajima, Y.; Yabuta, I.; Morisawa, G.; Kawamura, Y.; Nanamiya, H.; Imai, J.-i.; Takagi, M.

Preclinical species cross-reactivity data can understate human off-tumour binding for HER2-directed antibody-drug conjugates, with trastuzumab deruxtecan binding 38.8 percent of normal human tissue spots in a profile not conserved in cynomolgus monkey tissue.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The NexAb multiplex protein microarray platform reports that trastuzumab deruxtecan bound ERBB2-low cancer spots and 38.8 percent of normal human tissue spots, a profile not conserved in cynomolgus monkey tissue, while trastuzumab, trastuzumab emtansine and pertuzumab showed no cynomolgus cross-reactivity. The implied claim is that preclinical species cross-reactivity data can understate human off-tumour binding for HER2-directed antibody-drug conjugates. Two ERBB2 programs sit in the Claidex graph: a Phase 1 strategic discontinuation of a HER2-targeted STING agonist conjugate, xmt-2056-erbb2-her2-sting-agonist-adc-phase1-strategic-discontinuation, and a Phase 2 translational mismatch in HER2 exon 20 non-small cell lung carcinoma, poziotinib-erbb2-her2-exon20-nsclc-zenith20-phase2-translational-mismatch. Both involved a gap between the preclinical model and the human result, which is the same category of risk this platform paper measures. Teams running HER2 conjugates should treat a non-conserved monkey binding profile as a known blind spot rather than as reassurance.

Abstract excerpt

The NexAb multiplex protein microarray platform, comprising a 7,015-spot tissue lysate array and antigen-oriented protein arrays, was developed for preclinical tissue-binding and cross-reactivity assessment of therapeutic antibodies. Four anti-HER2 antibodies, trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-DXd), were profiled with integrated ERBB2 mRNA data. On antigen-oriented arrays, cell-synthesized HER2 bound trastuzumab and pertuzumab strongly and epitope-dependently, whereas wheat-germ HER2 showed no binding. On the tissue lysate array, trastuzumab and T-DM1 bound HER2-positive cancer cell lines and tumor tissues with nearly identical profiles (correlation coefficient r = 0.991), and T-DXd bound ERBB2-low cancer spots and 38.8% of normal human tissue spots, a profile not conserved in cynomolgus monkeys. Trastuzumab, T-DM1, and pertuzumab showed no cross-reactivity with cynomolgus monkey tissues, whereas T-DXd bound 3.1% of monkey tissue spots. NexAb enables quantitative cross-reactivity profiling relevant to preclinical safety evaluation.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.