A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors

Tolcher, Anthony W.; Berlin, Jordan; Cosaert, Jan; Kauh, John S.; Chan, Emily; Piha-Paul, Sarina A.; Amaya, Alex; Tang, Shande; Driscoll, Kyla E.; Kimbung, Richard; Kambhampati, Siva Rama Prasad; Gueorguieva, Ivelina; Hong, David S.

doi:10.1007/s00280-017-3245-5

Cited by 78 publications

(60 citation statements)

References 17 publications

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“…Neutralization of TGF- with M7824 can potentially increase therapeutic efficacy and reduce the safety concerns associated with other therapies targeting the TGF- pathway, such as anti-TGF- antibodies, anti-TGF- receptor antibodies, and TGF-RI kinase inhibitors (80)(81)(82). In a phase 1 study of an anti-TGF-RII human IgG1 monoclonal antibody (LY3022859), dose escalation beyond 25 mg (flat dose) was considered unsafe because of uncontrolled cytokine release, despite prophylactic treatment (83). In addition, in a phase 1 study of the TGF- antibody fresolimumab (GC1008), treatmentemergent cutaneous lesions with characteristics of keratoacanthomas (KAs) were observed, as well as a single case of squamous cell carcinoma (84).…”

Section: Discussionmentioning

confidence: 99%

Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β

et al. 2018

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Antibodies targeting immune checkpoints are emerging as potent and viable cancer therapies, but not all patients respond to these as single agents. Concurrently targeting additional immunosuppressive pathways is a promising approach to enhance immune checkpoint blockade, and bifunctional molecules designed to target two pathways simultaneously may provide a strategic advantage over the combination of two single agents. M7824 (MSB0011359C) is a bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the extracellular domain of human transforming growth factor-β (TGF-β) receptor II, which functions as a "trap" for all three TGF-β isoforms. We demonstrate that M7824 efficiently, specifically, and simultaneously binds PD-L1 and TGF-β. In syngeneic mouse models, M7824 suppressed tumor growth and metastasis more effectively than treatment with either an anti-PD-L1 antibody or TGF-β trap alone; furthermore, M7824 extended survival and conferred long-term protective antitumor immunity. Mechanistically, the dual anti-immunosuppressive function of M7824 resulted in activation of both the innate and adaptive immune systems, which contributed to M7824's antitumor activity. Finally, M7824 was an effective combination partner for radiotherapy or chemotherapy in mouse models. Collectively, our preclinical data demonstrate that simultaneous blockade of the PD-L1 and TGF-β pathways by M7824 elicits potent and superior antitumor activity relative to monotherapies.

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Section: Discussionmentioning

confidence: 99%

Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β

et al. 2018

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“…Pirfenidone, another small molecule, is also discussed to be involved in inhibition of TGFBR2 [57]. LY3022859, an anti-TGFBR2 IgG1 monoclonal antibody was developed by Eli Lilly Company and was investigated in several Phase I trials but was not further propagated because of clinical immune side effects (uncontrolled cytokine release) [58]. To date it remains unclear whether these side effects were due to reaction to antibody-protein epitopes or due to a complete shut-down of TGFβ signaling.…”

Section: Discussionmentioning

confidence: 99%

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Kuespert

Heydn

Peters

et al. 2020

IJMS

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Antisense Oligonucleotides (ASOs) are an emerging drug class in gene modification. In our study we developed a safe, stable, and effective ASO drug candidate in locked nucleic acid (LNA)-gapmer design, targeting TGFβ receptor II (TGFBR2) mRNA. Discovery was performed as a process using state-of-the-art library development and screening. We intended to identify a drug candidate optimized for clinical development, therefore human specificity and gymnotic delivery were favored by design. A staggered process was implemented spanning in-silico-design, in-vitro transfection, and in-vitro gymnotic delivery of small batch syntheses. Primary in-vitro and in-vivo toxicity studies and modification of pre-lead candidates were also part of this selection process. The resulting lead compound NVP-13 unites human specificity and highest efficacy with lowest toxicity. We particularly focused at attenuation of TGFβ signaling, addressing both safety and efficacy. Hence, developing a treatment to potentially recondition numerous pathological processes mediated by elevated TGFβ signaling, we have chosen to create our data in human lung cell lines and human neuronal stem cell lines, each representative for prospective drug developments in pulmonary fibrosis and neurodegeneration. We show that TGFBR2 mRNA as a single gene target for NVP-13 responds well, and that it bears great potential to be safe and efficient in TGFβ signaling related disorders.

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“…153 TR1 or IMC-TR1 (LY3022859) is another fully human anti-TβRII monoclonal antibody developed by Eli-Lilly & Co, tested in clinical trials in patients with advanced solid tumors. 157 As regards liver tumors, Dituri et al reported a different response in an HCC preclinical model between IMC-TR1 and galunisertib (LY2157299, Eli-Lilly & Co), suggesting that receptor expression on tumor cells is only one aspect in the patients selection approach and microenvironment, and that immune cell expression for this receptor should be taken into consideration. 158…”

Section: Inhibiting the Tgf-β Signaling Pathwaymentioning

confidence: 99%

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

et al. 2018

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Therapeutic attempts to treat hepatocellular carcinoma (HCC) frequently result in a poor response or treatment failure. The efficacy of approved drugs and survival expectancies is affected by an ample degree of variability that can be explained at least in part by the enormous between-patient cellular and molecular heterogeneity of this neoplasm. Transforming growth factor-β (TGF-β) is hyperactivated in a large fraction of HCCs, where it influences complex interactive networks covering multiple cell types and a plethora of other local soluble ligands, ultimately establishing several malignancy traits. This cytokine boosts the invasiveness of cancerous epithelial cells through promoting the epithelial-to-mesenchymal transition program, but also skews the phenotype of immune cells toward a tumor-supporting status. Here, we discuss recent strategies pursued to offset TGF-β-dependent processes that promote metastatic progression and immune surveillance escape in solid cancers, including HCC. Moreover, we report findings indicating that TGF-β reduces the expression of the proinflammatory factors CCL4 and interleukin-1β (IL-1β in human ex vivo treated HCC tissues. While this is consistent with the anti-inflammatory properties of TGF-β, whether it is an outright tumor promoter or suppressor is still a matter of some debate. Indeed, IL-1β has also been shown to support angiogenesis and cell invasiveness in some cancers. In addition, we describe an inhibitory effect of TGF-β on the secretion of CCL2 and CXCL1 by HCC-derived fibroblasts, which suggests the existence of an indirect stroma-mediated functional link between TGF-β and downstream immunity.

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A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors

Cited by 78 publications

References 17 publications

Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β

Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

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