Reference Detail

Ref Type

Journal Article

PMID

(30563566)

Authors

Fromm G, de Silva S, Johannes K, Patel A, Hornblower JC, Schreiber TH

Title

Agonist redirected checkpoint, PD1-Fc-OX40L, for cancer immunotherapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal for immunotherapy of cancer	6	1	2018 Dec 18	149	J Immunother Cancer

URL

Abstract Text

Simultaneous blockade of immune checkpoint molecules and co-stimulation of the TNF receptor superfamily (TNFRSF) is predicted to improve overall survival in human cancer. TNFRSF co-stimulation depends upon coordinated antigen recognition through the T cell receptor followed by homotrimerization of the TNFRSF, and is most effective when these functions occur simultaneously. To address this mechanism, we developed a two-sided human fusion protein incorporating the extracellular domains (ECD) of PD-1 and OX40L, adjoined by a central Fc domain, termed PD1-Fc-OX40L. The PD-1 end of the fusion protein binds PD-L1 and PD-L2 with affinities of 2.08 and 1.76 nM, respectively, and the OX40L end binds OX40 with an affinity of 246 pM. High binding affinity on both sides of the construct translated to potent stimulation of OX40 signaling and PD1:PD-L1/L2 blockade, in multiple in vitro assays, including improved potency as compared to pembrolizumab, nivolumab, tavolixizumab and combinations of those antibodies. Furthermore, when activated human T cells were co-cultured with PD-L1 positive human tumor cells, PD1-Fc-OX40L was observed to concentrate to the immune synapse, which enhanced proliferation of T cells and production of IL-2, IFNγ and TNFα, and led to efficient killing of tumor cells. The therapeutic activity of PD1-Fc-OX40L in established murine tumors was significantly superior to either PD1 blocking, OX40 agonist, or combination antibody therapy; and required CD4+ T cells for maximum response. Importantly, all agonist functions of PD1-Fc-OX40L are independent of Fc receptor cross-linking. Collectively, these data demonstrate a highly potent fusion protein that is part of a platform, capable of providing checkpoint blockade and TNFRSF costimulation in a single molecule, which uniquely localizes TNFRSF costimulation to checkpoint ligand positive tumor cells.

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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
SL-279252	SL-279252	1	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SL-279252		SL 279252\|SL279252\|PD1-Fc-OX40L	Immune Checkpoint Inhibitor 149	SL-279252 is a chimeric fusion protein that consists of the extracellular domains of PD-1 (PDCD1) and OX40L (TNFSF4) linked by an Fc domain, which may result in both immune checkpoint inhibition and TNF receptor activation, leading to increased antitumor immune response (PMID: 30563566).

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
CD274 positive	lung non-small cell carcinoma	sensitive	SL-279252	Preclinical - Cell culture	Actionable	In a preclinical study, SL-279252 treatment coupled the activation of T-lymphocytes with induction of tumor cell apoptosis in a coculture of CD274-positive non-small cell lung cancer cells and CD3-positive T-lymphocytes (PMID: 30563566).	30563566