Journal Article

DKFZ-2026-01783

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png An anti-PMEL antibody-drug conjugate with a Gq/11 inhibitor payload in GNAQ/GNA11-mutant melanomas: a phase 1 trial.

Carlino, M. S. ; Kapiteijn, E. ; Piperno-Neumann, S. ; Sullivan, R. J. ; Carvajal, R. ; Dummer, R. ; Gromke, T. ; Hassel, J.DKFZ* ; Kee, D. ; Ramelyte, E. ; Shoushtari, A. N. ; Wei, A. Z. ; Enk, A. ; Handel, E. E. ; Montazeri, K. ; Ramon-Patino, J. ; Richly, H. ; Rodrigues, M. ; Sandhu, S. ; Smithy, J. ; Speetjens, F. M. ; Milanez-Almeida, P. ; Chaudhury, A. ; Hoffmaster, K. ; Ising, M. ; Otero, J. A. ; RamKumar, T. ; Reynolds, A. ; Sharaby, S. ; Werner, L. ; Yerramilli-Rao, P. ; Calvo, E.

2026
Springer Nature [New York, NY]

Abstract: Metastatic uveal melanoma (mUM) is an aggressive cancer with limited treatment options; 85-90% of tumors harbor activating GNAQ and GNA11 mutations. Uveal melanoma cells also express PMEL (also known as PMEL17 or gp100), a melanocyte lineage antigen. DYP688, a novel biology-matched antibody-drug conjugate, binds surface PMEL and delivers the potent Gαq/Gα11 (Gq/11) inhibitor SDZ475 as payload by internalization. This dose-escalating first-in-human phase 1 study of DYP688 in patients with metastatic uveal melanoma and other GNAQ/GNA11-mutant melanomas assessed safety as the primary endpoint and pharmacokinetics and preliminary antitumor activity as secondary endpoints. Sixty-six patients received varying DYP688 doses and schedules. Grade 3 treatment-related adverse events occurred in five patients (7.6%), including one dose-limiting toxicity of grade 3 hypotension. Objective responses were seen in 13 out of 66 patients (19.7%) and tumor reduction in 47 out of 66 patients (71.2%). Median progression-free survival was 7.2 (95% CI: 5.3-7.8) months. In summary, DYP688 was well tolerated and showed preliminary efficacy, supporting this novel therapeutic approach. ClinicalTrials.gov identifier: NCT05415072 .

Note: #NCTZFB9# / epub

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Contributing Institute(s):

1. Koordinierungsstelle NCT Heidelberg (HD02)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 80 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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