Open AccessTargeting MICA/B with cytotoxic therapeutic antibodies leads to tumor control
Author(s) -
Mathieu Bléry,
Manel Mrabet-Kraiem,
Ariane Morel,
Florence Lhospice,
Delphine Brégeon,
Cécile Bonnafous,
Laurent Gauthier,
Benjamín Rossi,
Romain Remark,
Stéphanie Cornen,
Nadia Anceriz,
Nicolas Viaud,
Sylvia Trichard,
Sabrina Carpentier,
Alix Joulin-Giet,
Gwendoline Grondin,
Veronika Liptakova,
Young-Hoon Kim,
Laurent Daniel,
Aurélie Haffner,
Nicolas Macagno,
Laurent Pouyet,
Ivan Perrot,
Carine Paturel,
Yannis Morel,
Alexander Steinle,
François Romagné,
Émilie Narni-Mancinelli,
Éric Vivier
Publication year - 2021
Publication title -
open research europe
Language(s) - English
Resource type - Journals
ISSN - 2732-5121
DOI - 10.12688/openreseurope.13314.1
Subject(s) - biology , cancer research , cytotoxic t cell , monoclonal antibody , antibody , nkg2d , immunology , in vitro , genetics
Background: MICA and MICB are tightly regulated stress-induced proteins that trigger the immune system by binding to the activating receptor NKG2D on cytotoxic lymphocytes. MICA and MICB are highly polymorphic molecules with prevalent expression on several types of solid tumors and limited expression in normal/healthy tissues, making them attractive targets for therapeutic intervention. Methods: We have generated a series of anti-MICA and MICB cross-reactive antibodies with the unique feature of binding to the most prevalent isoforms of both these molecules. Results: The anti-MICA and MICB antibody MICAB1, a human IgG1 Fc-engineered monoclonal antibody (mAb), displayed potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of MICA/B-expressing tumor cells in vitro . However, it showed insufficient efficiency against solid tumors in vivo , which prompted the development of antibody-drug conjugates (ADC). Indeed, optimal tumor control was achieved with MICAB1-ADC format in several solid tumor models, including patient-derived xenografts (PDX) and carcinogen-induced tumors in immunocompetent MICAgen transgenic mice. Conclusions: These data indicate that MICA and MICB are promising targets for cytotoxic immunotherapy.