Abstract
Background. Bispecific antibodies that target tumors by engaging innate-like T cell subsets with inherent antitumor activity, such as Vγ9Vδ2-T and type 1 natural killer T (NKT) cells, may combine high therapeutic efficacy with limited off-tumor toxicity. Type 1 NKT cells respond to self and foreign (glyco)lipid antigens presented in the context of the MHC class I like molecule CD1d which is expressed on various malignancies. Vγ9Vδ2-T cells respond to intracellular accumulation of phosphoantigens in cancer cells by sensing conformational alterations in the butyrophilin (BTN) 2A1-3A1 complex. CD1d is expressed by the majority of patients with CLL and MM, while expression in AML is most pronounced on (myelo)monocytic subtypes.
Methods. LAVA-051 is a 27kD humanized bispecific single domain antibody (bsVHH) that directly engages CD1d and the Vδ2-TCR chain of Vγ9Vδ2-T cells. The anti-CD1d VHH specifically stabilizes the interaction between CD1d and the type 1 NKT cell TCR and thereby triggers strong activation of type 1 NKT cells (Nature Cancer 2020;1:1054-1065). Vγ9Vδ2-T and type 1 NKT effector cell activation, proliferation, cytokine production and target cell lysis were assessed in in vitro, ex vivo, and in vivo studies. Due to lack of cross reactivity of LAVA-051 with non-human primate (NHP) CD1d and Vγ9Vδ2-T cells, a cross-reactive surrogate bispecific engager was generated to assess tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) parameters.
Results. The CD1d-Vδ2 bsVHH LAVA-051 triggers activation of both Vγ9Vδ2-T and type 1 NKT cells (EC 50 4 pM for Vγ9Vδ2-T and 366 pM for type 1 NKT; induction of > 80% degranulation in 4h assays) and mediates potent killing of CD1d expressing tumor cells by engagement of Vγ9Vδ2-T and/or type 1 NKT cells (EC 50 1 pM for Vγ9Vδ2-T and 216 pM for type 1 NKT; > 85% target cell lysis in 16h assays at a low 1:2 E:T ratio). Further, LAVA-051 triggered pro-inflammatory cytokine production, proliferation of Vγ9Vδ2-T and type 1 NKT cells, and exerted substantial antitumor activity against patient AML, CLL and MM cells that express CD1d and improved survival in in vivo T-ALL, AML and MM mouse models. Multiple dose studies in NHP (7 daily doses up to 1 mg/kg iv) showed clear Vγ9Vδ2-T cell engagement and some cytokine release after the first administration, but no clinical, laboratory, or histopathological toxicity. Reflecting the low molecular size of this bispecific engager, PK studies revealed a short plasma half-life which was however compensated for by prolonged (up to 5 days) binding of the engager to peripheral blood Vγ9Vδ2-T cells allowing intermittent dosing.
Conclusions. In this study, we demonstrate that the CD1d-Vδ2 bsVHH LAVA-051 triggers activation of both type 1 NKT and Vγ9Vδ2-T cells, which translates directly into antitumor activity. Based on the expression of CD1d in CLL, MM, and AML, the strong preclinical activity of LAVA-051 against CD1d-expresssing tumors, and the favorable tolerability profile of the surrogate engager in NHP, LAVA-051 is currently evaluated in a first-in-human clinical Phase 1/2a study in patients with CD1d-expressing CLL, MM, or AML refractory to prior therapy (NCT04887259).
Disclosures
Lameris: Lava Therapeutics: Honoraria, Patents & Royalties, Research Funding. Ruben: Lava Therapeutics: Current Employment, Honoraria, Research Funding. Weerdt: LAVA Therapeutics: Research Funding. Roovers: LAVA Therapeutics: Current Employment, Current equity holder in publicly-traded company. van de Donk: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding. Broyl: Amgen: Honoraria; Bristol-Meyer Squibb: Honoraria; Celgene: Honoraria; Janssen Pharmaceuticals: Honoraria; Sanofi: Honoraria. Kater: Abbvie: Honoraria, Other: Ad Board, Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Riedl: LAVA THerapeutics: Current Employment, Current equity holder in publicly-traded company; Genmab BV: Current equity holder in publicly-traded company. Iglesias: LAVA therapeutics: Current Employment. Winograd: LAVA therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Celgene: Ended employment in the past 24 months; BMS: Current equity holder in publicly-traded company. Adang: LAVA therapeutics: Current Employment, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. de Gruijl: LAVA therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; DCPrime: Membership on an entity's Board of Directors or advisory committees; Macrophage Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Idera Pharmaceuticals: Research Funding; ORCA Therapeutics: Patents & Royalties. Parren: Lava Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Sparring Bioconsult BV: Membership on an entity's Board of Directors or advisory committees; Genmab: Patents & Royalties; Roche: Consultancy. Vliet: Lava Therapeutics: Current Employment, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Glycostem: Research Funding.
Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabinein vitroand in orthotopic mouse model of human pancreatic cancer