Authors
Emma Larsson, Moeen Ud-Din, Athanasios Bitzios, Enrique Recasens Pérez-Vera, Hanna Tegel, Anna Orlova, Vladimir Tolmachev, Anzhelika Vorobyeva, Sophia Hober
Published in
Molecular pharmaceutics. Volume 23. Issue 9. Pages 4743-4757. Sep 07, 2026.
Abstract
Folate receptor alpha (FRα) is frequently overexpressed in ovarian cancer while showing limited expression in healthy tissues. Targeting of FRα has been extensively investigated using antibody-based therapies but less so with small scaffold proteins. Small scaffold proteins represent an alternative approach with potential advantages such as site-specific conjugation and deep tumor penetration but are limited by a short half-life. Here, we describe the development of a dual-surfaced ADAPT scaffold protein (6 kDa) with simultaneous bispecificity for FRα and albumin. Using combinatorial libraries and phage display, we identified a candidate, termed ADAPT22, with high isoform selectivity and subnanomolar affinity for FRα (KD = 0.8 nM), paired with a low nanomolar affinity for albumin (KD = 2.4 nM). Importantly, ADAPT22 is able to interact with both targets simultaneously, truly combining extended retention in blood via albumin association and tumor targeting via FRα within a single-domain protein. The simultaneous nature was verified in vitro to soluble proteins and to FRα-positive cells and in vivo using a mouse xenograft model. In mice, ADAPT22 demonstrated markedly extended blood retention, reduced renal uptake, and specific accumulation in FRα-positive tumors, confirming simultaneous dual-surface binding. To the best of our knowledge, this is the smallest half-life extended affinity protein designed for therapeutic targeting of FRα.
PMID:
42704121
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.
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