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IgG2 (or its h2 region) may be better backbone for agonist immuno Abs
http://t.co/qIInGZ22H9 http://t.co/89EV5M39Ma #cancer #immunotherapy
Summary
Monoclonal antibody (mAb) drugs that stimulate antitumor immunity are transforming cancer treatment but require optimization for maximum clinical impact. Here, we show that, unlike other immunoglobulin isotypes, human IgG2 (h2) imparts FcγR-independent agonistic activity to immune-stimulatory mAbs such as anti-CD40, -4-1BB, and -CD28. Activity is provided by a subfraction of h2, h2B, that is structurally constrained due its unique arrangement of hinge region disulfide bonds. Agonistic activity can be transferred from h2 to h1 by swapping their hinge and CH1 domains, and substitution of key hinge and CH1 cysteines generates homogenous h2 variants with distinct agonistic properties. This provides the exciting opportunity to engineer clinical reagents with defined therapeutic activity regardless of FcγR expression levels in the local microenvironment.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).
Via Krishan Maggon
Highlights
•Immunomodulatory mAbs are revolutionizing cancer treatment but need optimization•Agonistic mAbs are generally dependent on FcγR crosslinking for activity•An unusual disulfide hinge configuration in human IgG2 is superagonistic•IgG2 engineering provides therapeutics that are active in tissues devoid of FcγR