Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors

Edward Hammond,Carleen Cullinane,Paul Handley,Nicole M Haynes,Yiping Yang,Keith Dredge,Tomislav Karoli,Todd V Brennan,Darryn Bampton,Fleur Lanksheer,Liwen Lin

doi:10.1186/s40425-018-0363-5

Edward Hammond, Carleen Cullinane + Show 9 more

Open Access

https://doi.org/10.1186/s40425-018-0363-5

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Abstract

BackgroundPixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet also stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells. Preclinically, pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas its immunostimulatory activity on DCs is through the MyD88-dependent TLR9 pathway. Pixatimod recently completed a Phase Ia monotherapy trial in advanced cancer patients.MethodsTo characterize the safety of pixatimod administered by intravenous (IV) infusion, a one month toxicology study was conducted to support a Phase Ia monotherapy clinical trial. The relative exposure (AUC) of pixatimod across relevant species was determined and the influence of route of administration on the immunomodulatory activity was also evaluated. Finally, the potential utility of pixatimod in combination with PD-1 inhibition was also investigated using the syngeneic 4T1.2 breast cancer model.ResultsThe nonclinical safety profile revealed that the main toxicities associated with pixatimod are elevated cholesterol, triglycerides, APTT, decreased platelets and other changes symptomatic of modulating the immune system such as pyrexia, changes in WBC subsets, inflammatory changes in liver, spleen and kidney. Though adverse events such as fever, elevated cholesterol and triglycerides were reported in the Phase Ia trial, none were considered dose limiting toxicities and the compound was well tolerated up to 100 mg via IV infusion. Exposure (AUC) up to 100 mg was considered proportional with some accumulation upon repeated dosing, a phenomenon also noted in the toxicology study. The immunomodulatory activity of pixatimod was independent of the route of administration and it enhanced the effectiveness of PD-1 inhibition in a poorly immunogenic tumor model.ConclusionsPixatimod modulates innate immune cells but also enhances T cell infiltration in combination with anti-PD-1 therapy. The safety and PK profile of the compound supports its ongoing development in a Phase Ib study for advanced cancer/pancreatic adenocarcinoma with the checkpoint inhibitor nivolumab (Opdivo®).Trial registrationClinicalTrials.gov Identifier: NCT02042781. First posted: 23 January, 2014 - Retrospectively registered.

Highlights

Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells
Nonclinical and clinical safety The toxicity profile of pixatimod in beagle dogs compromised of some findings consistent with that of an immunomodulatory agent
It is of interest to note that significant elevations in body temperature was apparent following the first dose of pixatimod but the effect appeared to dissipate upon repeat dosing by day 30 (Fig. 2a)

Summary

Introduction

Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells. Pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas its immunostimulatory activity on DCs is through the MyD88-dependent TLR9 pathway. Pixatimod inhibits the infiltration of tumor-associated macrophages (TAMs) [9, 10] but, it stimulates dendritic cells (DCs) [11]. In addition to the reported activity of pixatimod on TAMs and M2 macrophages [9, 10], the compound exerts a strong immunostimulatory activity on CD11c+ DCs, via toll-like receptor 9 (TLR9) and IL-12 leading to activation of IFN-γ producing natural killer (NK) cells [11]. Pixatimod’s immunomodulatory effects on these myeloid cells enhance innate immunity and may drive adaptive immune responses depending on the context (e.g. presence of tumor antigens, combination with PD-1 inhibitors)

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