NVG-111, a novel ROR1xCD3 bispecific antibody for non-Hodgkin lymphoma.

Abstract

7549 Background: Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a type I transmembrane protein is highly expressed on an array of haematological and solid tumours. NVG-111 is a humanised, tandem scFv ROR1xCD3 bispecific antibody previously shown to elicit potent killing of tumour cells in vitro and in vivo by engaging a membrane-proximal epitope in the Wnt5a-binding Frizzled domain of ROR1 and redirecting T cell activity. The in vitro potency and pharmacodynamic responses to NVG-111 were assessed to support progression to a first-in-human study. Methods: The potency of NVG-111 in vitro was determined by evaluating the concentration response for cytotoxicity, T cell activation, and cytokine release in co-cultured Jeko-1 and unstimulated human T cells. Comparative data were generated for the marketed CD19xCD3 bispecific antibody, blinatumomab. Potency data for NVG-111 were used together with allometric scaling from murine PK studies to inform planned clinical doses. Results: NVG-111 demonstrated T cell-dependent cytotoxicity, T cell activation and levels of cytokine release similar in potency to blinatumomab. Cytotoxic responses of both NVG-111 and blinatumomab were more potent than T cell activation and cytokine release. Dose response curves for NVG-111 showed a decrease in activity beyond the concentration of maximal response (ie “hook effect”). We hypothesise this is due to receptor saturation, inhibiting synapse formation. NVG-111 has progressed to a Phase 1/2 first-in-human study in patients with debulked, relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), the drug given as add-on to ≥2nd line therapy with a Bruton’s tyrosine kinase inhibitor, or venetoclax. Phase 1 includes escalating doses of 0.3 to 360 µg/day via continuous infusion over 3 cycles (each 21 days on, 7 days off) to establish safety, PK, pharmacodynamics (PD) and recommended phase 2 dose (RP2D). Predicted exposure at 0.3 µg/day is ̃EC20 for cytotoxicity in vitro and below the lowest EC10 for cytokine release. PD biomarkers in the study include systemic cytokines. Phase 2 will study efficacy and safety of the RP2D in CLL and MCL, with primary endpoint complete response rate; other efficacy endpoints include minimal residual disease and progression free survival. Conclusions: NVG-111 shows potent T-cell mediated lymphoma cell cytotoxicity in vitro at concentrations well below those associated with extensive cytokine release. NVG-111 is in an ongoing Phase 1/2 study and may present a novel option for adoptive immunotherapy in patients with non-Hodgkin lymphoma and potentially other cancers. Clinical trial information: 2020-000820-20. [Table: see text]

The Role of Bispecific Antibodies in Non-Hodgkin’s Lymphoma: From Structure to Prospective Clinical Use

“…Patients are ≥2nd line therapy with a Bruton's tyrosine kinase inhibitor, or venetoclax (clinical trial information: 2020-000820-20). Results are pending [58].…”

“…NVG-111 is a humanized, tandem scFv bsAb binding ROR1 and CD3 and previously shown to be a potent tumor cell killer in vitro. In vivo it has also been shown to engage a ROR1 membrane-proximal epitope in the Wnt5abinding Frizzled domain and redirect T-cell activity [58]. An ongoing phase 1/2 study in patients with R/R chronic lymphocytic leukemia (CLL) and MCL is evaluating an escalated doses schedule (of 0.3 to 360 µg/day) via continuous infusion over 3 cycles (each 21 days on, 7 days off).…”

How receptor tyrosine kinase‐like orphan receptor 1 meets its partners in chronic lymphocytic leukemia

“…NVG-111 is a bispecific antibody that can simultaneously bind both ROR1 and CD3 molecules used to promote the activation of cytotoxic T cells through the T cell CD3 complex and selectively target the activated T cells to ROR1-positive malignant cells, with promising results in CLL and solid tumors in preclinical models. [106][107][108] CAR-T cells targeting ROR1 proved effective outcomes in patients with ROR1 pos hematological and solid malignancies. 28,98,109 The application of small-molecule TK inhibitors (TKIs), ATPcompetitive inhibitors, is one of the most effective approaches for cancer treatment targeting the catalytic domains in TKs.…”

“…Another strategy of targeting ROR1 includes BiTEs, genetically engineered recombinant antibodies that can simultaneously bind two different epitopes or antigens. NVG‐111 is a bispecific antibody that can simultaneously bind both ROR1 and CD3 molecules used to promote the activation of cytotoxic T cells through the T cell CD3 complex and selectively target the activated T cells to ROR1‐positive malignant cells, with promising results in CLL and solid tumors in preclinical models 106–108 …”

Receptor tyrosine kinase-like orphan receptor 1: A novel antitumor target in gastrointestinal cancers

“…NVG-111 is the first BiAb that utilized the inherent cytotoxicity of T cells. Ongoing clinical trials of NVG-111 have shown promising results in both CLL and solid tumors, with favorable cytotoxicity[ 48 ]. Another bispecific T-cell splicer, SFG.…”