Reference Detail

Ref Type

Journal Article

PMID

(32341336)

Authors

Oostindie SC, van der Horst HJ, Kil LP, Strumane K, Overdijk MB, van den Brink EN, van den Brakel JHN, Rademaker HJ, van Kessel B, van den Noort J, Chamuleau MED, Mutis T, Lindorfer MA, Taylor RP, Schuurman J, Parren PWHI, Beurskens FJ, Breij ECW

Title

DuoHexaBody-CD37®, a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood cancer journal	10	3	2020 Apr 28	30	Blood Cancer J

URL

Abstract Text

Tetraspanin CD37 has recently received renewed interest as a therapeutic target for B-cell malignancies. Although complement-dependent cytotoxicity (CDC) is a powerful Fc-mediated effector function for killing hematological cancer cells, CD37-specific antibodies are generally poor inducers of CDC. To enhance CDC, the E430G mutation was introduced into humanized CD37 monoclonal IgG1 antibodies to drive more efficient IgG hexamer formation through intermolecular Fc-Fc interactions after cell surface antigen binding. DuoHexaBody-CD37, a bispecific CD37 antibody with the E430G hexamerization-enhancing mutation targeting two non-overlapping epitopes on CD37 (biparatopic), demonstrated potent and superior CDC activity compared to other CD37 antibody variants evaluated, in particular ex vivo in patient-derived chronic lymphocytic leukemia cells. The superior CDC potency was attributed to enhanced IgG hexamerization mediated by the E430G mutation in combination with dual epitope targeting. The mechanism of action of DuoHexaBody-CD37 was shown to be multifaceted, as it was additionally capable of inducing efficient antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro. Finally, potent anti-tumor activity in vivo was observed in cell line- and patient-derived xenograft models from different B-cell malignancy subtypes. These encouraging preclinical results suggest that DuoHexaBody-CD37 (GEN3009) may serve as a potential therapeutic antibody for the treatment of human B-cell malignancies.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
GEN3009	GEN3009	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
GEN3009		GEN-3009\|GEN 3009\|DuoHexaBody-CD37	CD37 Antibody 8	GEN3009 is a bivalent CD37 monoclonal antibody with enhanced hexamerization ability, which potentially induces antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity, and results in reduced tumor growth (PMID: 32341336).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References