9GOY

Crystal structure of Fab E2-RecA in complex with CD38

9GOY の概要

• エントリーDOI: 10.2210/pdb9goy/pdb
• 分子名称: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1, Fab E2-RecA heavy chain, Fab E2-RecA light chain, ... (6 entities in total)
• 機能のキーワード: fab, biparatopic bispecific antibody, antibody, innate cell modulator, cd38, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 78445.96

構造登録者

Dreyfus, C.,Fritz, G. (登録日: 2024-09-06, 公開日: 2025-02-12)

主引用文献

Loyau, J.,Monney, T.,Montefiori, M.,Bokhovchuk, F.,Streuli, J.,Blackburn, M.,Goepfert, A.,Caro, L.N.,Chakraborti, S.,De Angelis, S.,Grandclement, C.,Blein, S.,Mbow, M.L.,Srivastava, A.,Perro, M.,Sammicheli, S.,Zhukovsky, E.A.,Dyson, M.,Dreyfus, C.
Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidity.
Mabs, 17:2457471-2457471, 2025

PubMed Abstract: ISB 1442 is a bispecific biparatopic antibody in clinical development to treat hematological malignancies. It consists of two adjacent anti-CD38 arms targeting non-overlapping epitopes that preferentially drive binding to tumor cells and a low-affinity anti-CD47 arm to enable avidity-induced blocking of proximal CD47 receptors. We previously reported the pharmacology of ISB 1442, designed to reestablish synthetic immunity in CD38+ hematological malignancies. Here, we describe the discovery, optimization and characterization of the ISB 1442 antigen binding fragment (Fab) arms, their assembly to 2 + 1 format, and present the high-resolution co-crystal structures of the two anti-CD38 Fabs, in complex with CD38. This, with biophysical and functional assays, elucidated the underlying mechanism of action of ISB 1442. In solution phase, ISB 1442 forms a 2:2 complex with CD38 as determined by size-exclusion chromatography with multi-angle light scattering and electron microscopy. The predicted antibody-antigen stoichiometries at different CD38 surface densities were experimentally validated by surface plasmon resonance and cell binding assays. The specific design and structural features of ISB 1442 enable: 1) enhanced trans binding to adjacent CD38 molecules to increase Fc density at the cancer cell surface; 2) prevention of avid cis binding to monomeric CD38 to minimize blockade by soluble shed CD38; and 3) greater binding avidity, with a slower off-rate at high CD38 density, for increased specificity. The superior CD38 targeting of ISB 1442, at both high and low receptor densities, by its biparatopic design, will enhance proximal CD47 blockade and thus counteract a major tumor escape mechanism in multiple myeloma patients.

PubMed: 39882744
DOI: 10.1080/19420862.2025.2457471

実験手法

X-RAY DIFFRACTION (2.7 Å)