A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells

Abstract

The principal antitumor immune response is mediated through the activation of type 1 cytotoxic (Tc1) CD8 T cells, NK cells, and monocytes/macrophages. In this study, we investigated the potency of a clinical-grade soluble form of lymphocyte activation gene-3 protein (IMP321), a physiological high-affinity MHC class II binder, at inducing in PBMCs an appropriate cytotoxic-type response in short-term ex vivo assays. We found that IMP321 binds to a minority (<10%) of MHC class II + cells in PBMCs, including all myeloid dendritic cells, and a small fraction of monocytes. Four hours after addition of IMP321 to PBMCs, these myeloid cells produce TNF-α and CCL4 as determined by intracellular staining. At 18 h, 1% of CD8+ T cells and 3.7% NK cells produce Tc1 cytokines such as IFN-γ and/or TNF-α (mean values from 60 blood donors). Similar induction was observed in metastatic cancer patient PBMCs, but the values were lower for the NK cell subset. Early APC activation by IMP321 is needed for this Tc1-type activation because pure sorted CD8+ T cells could not be activated by IMP321. Only Ag-experienced, fully differentiated granzyme+ CD8 T cells (effector and effector memory but not naive or central memory T cells) are induced by IMP321 to full Tc1 activation. In contrast to IMP321, TLR1-9 agonists induce IL-10 and are therefore unable to induce this Tc1 IFN-γ+ response. Thus, IMP321 has many properties that confirm its potential to be a new class of immunopotentiator in cancer patients.

A Phase I Pharmacokinetic and Biological Correlative Study of IMP321, a Novel MHC Class II Agonist, in Patients with Advanced Renal Cell Carcinoma

“…CD40L has been tested in phase I trials (4) but clinical development has been stopped due to secondary effects such as thrombosis induction (its receptor, CD40, is also expressed on platelets and endothelial cells). Thus, the soluble LAG-3Ig fusion protein (or IMP321) is the only protein that is presently available for this therapeutic approach (5)(6)(7)(8).…”

Emerging Immunotherapy Strategies in Breast Cancer

“…IMP321 is a soluble form of LAG-3, a protein expressed on activated T cells that binds MHC class II. In a preceding trial of IMP321 in metastatic renal cell carcinoma, IMP321 promoted favorable T H 1 lineage differentiation, cytokine release, T-cell effector priming and lymph node migration [62]. In this trial, IMP321 was delivered subcutaneously every 2 weeks with weekly 80 mg/m 2 intravenous paclitaxel.…”

Emerging Targets in Cancer Immunotherapy: Beyond CTLA-4 and PD-1

“…IMP321 is a clinical grade LAG-3-Ig recombinant fusion protein that antagonizes normal LAG-3 functioning [120]. In 2009 the results of the first Phase I study involving IMP321 alone was released.…”