CD40- and 41BB-specific antibody fusion proteins with PDL1 blockade-restricted agonism
Medler J, Kucka K, Melo V, Zhang T, Von Rotenhan S, Ulrich J, Bremer E, Hudecek M, Beilhack A, Wajant H (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 12
Pages Range: 1486-1499
Journal Issue: 4
DOI: 10.7150/thno.66119
Abstract
Background: A strategy to broaden the applicability of checkpoint inhibitors is the combined use with antibodies targeting the immune stimulatory receptors CD40 and 41BB. However, the use of anti-CD40 and anti-41BB antibodies as agonists is problematic in two ways. First, anti-CD40 and anti-41BB antibodies need plasma membrane-associated presentation by FcγR binding to exert robust agonism but this obviously limits their immune stimulatory efficacy by triggering ADCC, CDC or anti-inflammatory FcγRIIb activities. Second, off tumor activation of CD40 and 41BB may cause dose limiting systemic inflammation. Methods: To overcome the FcγR-dependency of anti-41BB and anti-CD40 antibodies, we genetically fused such antibodies with a PDL1-specific blocking scFv as anchoring domain to enable FcγR-independent plasma membrane-associated presentation of anti-CD40- and anti-41BB antibodies. By help of GpL-tagged variants of the resulting bispecific antibodies, binding to their molecular targets was evaluated by help of cellular binding studies. Membrane PDL1-restricted engagement of CD40 and 41BB but also inhibition of PDL1-induced PD1 activation were evaluated in coculture assays with PDL1-expressing tumor cell lines and 41BB, CD40 and PD1 responsible cell lines or T-cells. Results: The binding properties of the bispecific antibody fusion proteins remained largely unchanged compared to their parental molecules. Upon anchoring to membrane PDL1, the bispecific antibody fusion proteins activated CD40/41BB signaling as efficient as the parental anti-CD40/anti-41BB antibodies when bound to FcγRs or cells expressing membrane-bound CD40L/41BBL. PD1 inhibition remained intact and the anti-41BB fusion protein thus showed PDL1-restricted costimulation of T-cells activated in vitro with anti-CD3 or a BiTe. Conclusions: Targeting of anti-CD40 and anti-41BB fusion proteins to membrane PDL1 with a blocking PDL1 scFv links PD1-PDL1 checkpoint blockade intrinsically with engagement of CD40 or 41BB.
Involved external institutions
Universitätsklinikum Würzburg
Germany (DE)
University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen
Netherlands (NL)
Germany (DE)
University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen
Netherlands (NL)
How to cite
APA:
Medler, J., Kucka, K., Melo, V., Zhang, T., Von Rotenhan, S., Ulrich, J.,... Wajant, H. (2022). CD40- and 41BB-specific antibody fusion proteins with PDL1 blockade-restricted agonism. Theranostics, 12(4), 1486-1499. https://dx.doi.org/10.7150/thno.66119
MLA:
Medler, Juliane, et al. "CD40- and 41BB-specific antibody fusion proteins with PDL1 blockade-restricted agonism." Theranostics 12.4 (2022): 1486-1499.
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