GS-3583, a novel FLT3 agonist Fc fusion protein, to expand conventional dendritic cells in healthy volunteers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2559-2559
Author(s):  
Nishanthan Rajakumaraswamy ◽  
Anees Dauki ◽  
Michelle R. Kuhne ◽  
Torsten Trowe ◽  
Jing He ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Fusion Protein ◽  
Healthy Volunteers ◽  
Phase 1 ◽  
Vital Role ◽  
Controlled Study ◽  
Patients With Cancer ◽  
Fc Fusion Protein ◽  
Grade 3 ◽  
Dose Dependent

2559 Background: Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor specific CD8+ T cells and their recruitment to tumor microenvironment (TME). However, cDC1s are often underrepresented in the TME. Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L), a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to expansion of cDC1s in the periphery which can then be recruited into the TME. We hypothesize that FLT3 pathway stimulation using GS-3583, a FLT3 agonist Fc fusion protein, has the potential to promote T cell mediated anti-tumor activity. Methods: This was a first-in-human placebo-controlled study of GS-3583 in healthy volunteers to evaluate the safety, PK, and PD of escalating single doses (ranging from 75μg to 2000μg) of GS-3583. The study was blinded to the subjects and the investigator. Each dose cohort enrolled 8-12 healthy subjects who received GS-3583 or placebo as single IV infusion at 3:1 ratio. Subjects were observed in the phase 1 unit for 15 days and then for 12 weeks as outpatients. As part of the PD evaluation, we investigated the changes in the number of cDC1s and cDC subtype 2 (cDC2) cells. Results: As of 8th Feb 2021, selected safety, PK and PD data from the first 3 cohorts were available. GS-3583 was well tolerated and all subjects had been discharged. To date, there have been no serious or grade 3 or higher adverse events. Preliminary PK analysis suggested dose-dependent increase in GS-3583 exposure (AUC and Cmax). Preliminary PD analysis shows that administration of GS-3583 resulted in dose-dependent increases in cDC1/cDC2 cells that peaked at day 5 or day 8 and returned to baseline within three weeks of drug administration. Conclusions: GS-3583 was safe and well tolerated and induced dose dependent expansion of dendritic cells in the periphery. In patients with cancer, this increase in dendritic cells can be utilized to enhance anti-tumor responses to immuno-oncology therapies.[Table: see text]

scholarly journals 380 GS-3583, a novel FLT3 agonist Fc fusion protein, expands conventional dendritic cells in healthy volunteers

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A413-A414
Author(s):  
Nishanthan Rajakumaraswamy ◽  
Anees Dauki ◽  
Michelle Kuhne ◽  
Torsten Trowe ◽  
Winnie Weng ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Fusion Protein ◽  
Healthy Volunteers ◽  
Phase 1 ◽  
Vital Role ◽  
Controlled Study ◽  
Therapeutic Effects ◽  
Fc Fusion Protein ◽  
Quantitative Changes ◽  
Dose Dependent

BackgroundConventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor specific CD8+ T cells and their recruitment to tumor microenvironment (TME). However, cDC1s are often underrepresented in the TME. Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L), a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to expansion of cDC1s in the periphery which can then be recruited into the TME. FLT3 pathway stimulation using GS-3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T cell mediated anti-tumor activity. We sought to evaluate the pharmacodynamic (PD) effect of a single dose of GS-3583 in healthy volunteers alongside its safety. Herein, we present the updated results of the study.MethodsThis was a first-in-human, placebo-controlled study of GS-3583 in healthy volunteers to evaluate the safety, pharmacokinetics (PK), and PD of escalating single doses (ranging from 75 micrograms to 2000 micrograms) of GS-3583. The study was blinded to the subjects and the investigator. Each dose cohort enrolled 8–12 healthy subjects who received GS-3583 or placebo as single IV infusion at 3:1 ratio. Subjects were observed in the phase 1 unit for 15 days and then for 12 weeks as outpatients. As part of the PD evaluation, we investigated the changes in the number of cDC1 and cDC2 cells.ResultsAs of 2nd July 2021, selected safety, PK and PD data from all 4 cohorts were available. GS-3583 was well tolerated and all subjects had been discharged. To date, there have been no serious or grade 3 or higher adverse events. Preliminary PK analysis suggested dose-dependent increase in GS-3583 exposure (AUC and Cmax). Preliminary PD analysis shows that administration of GS-3583 resulted in temporary, dose-dependent increases in cDC1/cDC2 cells that peaked between days 5–11 (higher doses resulted in later peaks) and returned to baseline within 3 weeks of drug administration (table 1, figure 1).Abstract 380 Table 1Selected subject characteristics and pharmacodynamic resultsAbstract 380 Figure 1A) Comparison of cDC1 cell quantitative changes in cohorts 1–4; B) Comparison of cDC2 cell quantitative changes in cohorts 1–4ConclusionsGS-3583 infusion was well tolerated and induced dose dependent expansion of dendritic cells in the periphery in healthy volunteers. In patients with cancer, this increase in dendritic cells can be utilized to enhance anti-tumor therapeutic effects of immuno-oncology therapies.AcknowledgementsFunding provided by Gilead Sciences, Inc.Ethics ApprovalThe study received study site IRB/Ethics Committee approval prior to enrollment of subjects.

scholarly journals 846 Pre-clinical validation of a FLT3L-fusion protein for dendritic cell expansion and anti-tumor efficacy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A887-A887
Author(s):  
Michelle Kuhne ◽  
Hamlet Chu ◽  
Sarah Ng ◽  
Christopher Clarke ◽  
Brian Carr ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Fusion Protein ◽  
Tyrosine Kinase ◽  
Single Agent ◽  
Tumor Growth Inhibition ◽  
Cell Responses ◽  
Dose Dependent ◽  
Cell Death Protein

BackgroundThe ligand for the receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3) plays an importantrole in hematopoiesis. FLT3 signaling is required for the differentiation andexpansion of dendritic cells. In the context of cancer immunity, the conventional dendritic cellsubtype 1 (cDC1) are required for the generation of tumor-specific T cell responses in mousepreclinical models. In human tumors cDC1 are often underrepresented in thetumor microenvironment, supporting the hypothesis that therapeutically increasing their number via FLT3 pathway stimulation has the potential to promote T cell-mediated anti-tumor efficacy.MethodsGS-3583 is a fusion protein composed of the extracellular domain (ECD) of human FLT3 ligand(FLT3L) combined with a modified fragment crystallizable (Fc) region of human IgG4. GS-3583was designed to induce cDC1 expansion and subsequently promote tumor-reactive T cell priming, activation and recruitment into the tumor microenvironment. To evaluate the therapeutic efficacy of FLT3 stimulation in vivo, a mouse surrogate mGS-3583was designed using the ECD of mouse FLT3L fused to an engineered mouse IgG2a Fc withattenuated binding to mouse FcgRs.Results mGS-3583 bound to recombinant mouse FLT3 with an estimated affinity of 15 nM, and to mouse FLT3-expressing cells with an EC50 of 0.15 nM. In vivo, mGS-3583 showed single agent dose-dependent tumor growth inhibition (TGI) in tumors that correlated with peripheral and intratumoral cDC1 expansion. In tumors with no initial immune infiltration, mGS-3583 led to an influx of T cells into the tumors. In addition to single agent efficacy, mGS-3583 combined effectively with programmed cell death protein (ligand)-1 (PD(L)-1) pathway blockade.ConclusionsIn vivo expansion of dendritic cells can convert uninflamed (cold) tumors to immunologically active (hot) tumors and initiate productive anti-tumor immune responses. These findings support the development GS-3583 as a promising candidate for cancer immunotherapy.

Abstract 2009: ALX-0081 a Novel Anti-Thrombotic: Results of a Single-Dose Phase 1 Study in Healthy Volunteers and Further Development in Patients with Stable Angina Undergoing PCI

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jozef Bartunek ◽  
Emanuele Barbato ◽  
Josefin-Beate Holz ◽  
Kristof Vercruysse ◽  
Hans Ulrichts ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Dose Escalation ◽  
Stable Angina ◽  
Thrombus Formation ◽  
Phase 1 ◽  
Controlled Study ◽  
Double Blind ◽  
Phase Ib ◽  
Wide Range

Background : ALX-0081 is a bivalent Nanobody ® based on the variable domain of naturally occurring heavy-chain only antibodies. It binds with high affinity to the A1 domain of von Willebrand Factor (vWF) and thereby blocks the interactions between platelets and vascular collagen. It selectively prevents thrombus formation under high shear stress conditions. Aim : Test ALX-0081 single IV infusions (60 minutes) dosed from 0.5mg to 12mg total in 40 male healthy volunteers in double-blind, randomized, placebo controlled study and assess pharmacokinetic (PK), pharmacodynamic (PD), safety and immunogenicity. Results : ALX-0081 displayed non-linear pharmacokinetic properties, following a 2 compartment model. Ristocetin induced platelet aggregation (RIPA) was analyzed as marker for PD effect with full inhibition (defined as measured levels dropping <10%) observed at ALX-0081 concentrations of ~ 400ng/ml. All subjects dosed ≥ 2mg achieved full RIPA inhibition at 1h post-dosing for maximum of 12h. ALX-0081 treatment was well tolerated and safe, no signs of bleeding were reported and no immunogenic response was detected. Target related mild and transient reductions of vWF and FVIII plasma levels were observed and all events were fully reversible. Phase Ib study design : double-blind, randomized, placebo controlled, multiple ascending dose study. ALX-0081 added to standard anti-thrombotic regimen (ASA, clopidogrel, UFH) in patients with stable angina undergoing elective PCI. Single-dose escalation will be followed by multiple dosing (up to 4 doses in 24h). Dose escalation will be guided by safety and efficacy marker. Endpoints: safety, pharmacological profile, biomarker (RIPA, RICO and ACT) and early clinical outcome (MACE, IMR, molecular marker). Conclusion : ALX-0081 can be administered safely over a wide range of dose-regimen. First results of the phase Ib study in stable angina patients will be presented.

Phase 1b study of GAS6/AXL inhibitor (AVB-500) in recurrent, platinum-resistant ovarian carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5566-5566
Author(s):  
Katherine Cynthia Fuh ◽  
Michael A. Bookman ◽  
Robert L. Coleman ◽  
Thomas J Herzog ◽  
Premal H. Thaker ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Pegylated Liposomal Doxorubicin ◽  
Prior Therapy ◽  
Platinum Resistant ◽  
Pathway Activation ◽  
Potential Biomarker ◽  
Fc Fusion Protein ◽  
Phase 1B ◽  
Grade 3 ◽  
Trough Levels

5566 Background: AVB-500 is a first-in-class Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. Both GAS6 and AXL are highly expressed in high-grade serous ovarian cancer (HSGOC). This study evaluated safety, tolerability, and preliminary efficacy of AVB-500 in combination with pegylated liposomal doxorubicin (PLD) and paclitaxel (Pac) and determine the recommended Phase 2 dose (RP2D). Methods: Patients were enrolled in escalating dose cohorts of AVB-500 10mg/kg to 20mg/kg q2 weeks in combination with weekly Pac 80mg/m2 D1, 8, 15 q28 days or PLD 40mg/m2 D1 q28 days and assess for safety, pharmacokinetics, pharmacodynamics, and response by investigator, via RECIST v1.1. Results: A total of 53 patients with platinum-resistant HGSOC (PROC) were enrolled. A total of 23 patients received Pac + AVB-500 and 30 patients received PLD + AVB-500. Grade 3 or 4 treatment-related adverse events were observed in 4/23 (17%) and 2/30 (7%) PAC and PLD, respectively. No patients discontinued therapy due to an adverse event. Most events were related to known chemotherapy side effects. RP2D was identified as 15mg/kg. Confirmed overall response rate (ORR) with Pac+AVB-500 was 35% (8/23) including 2 CRs and 11% (3/28) in the PLD+AVB-500 subgroup. ORR was 19% (3/16) in patients with platinum free interval (PFI) of < 3 months versus (vs) 23% (8/35) in patients with PFI of 3-6 months. ORR was 11% (2/18) in patients with 1 prior treatment vs 27% (9/33) in patients with 2-3 prior lines of therapy. ORR in patients without prior bevacizumab was 33% (9/27) vs 8% (2/24) in those with prior bevacizumab. Patients treated with Pac combination and whose AVB-500 trough levels were above the minimal efficacious concentration (MEC) of 13.8mg/L achieved the greatest benefit with ORR, median PFS, and median OS of 43% (6/14), 3.9 months, and 17.8 months vs 22% (2/9), 2.8 months, and 8.7 months observed in those whose trough was below the MEC. Among the Pac treated subgroup, the ORR was 47% (13% CR) vs 0% for those with sAXL/GAS6 ratios > 0.773 compared to ratios <0.773. 67% of patients had baseline sAXL/GAS6 > 0.773. Conclusions: AVB-500 is a novel Fc fusion protein that binds the GAS6 ligand and inhibits AXL signaling. AVB-500 was well-tolerated in combination with Pac or PLD. This Ph1b trial suggested a higher ORR in the Pac treated subgroup, with C1D15 trough levels > 13.8mg/L (most consistently achieved at the 15mg/kg dose level). Exploratory analyses suggested that improved ORR may be observed in patients who have not been exposed to bevacizumab. The serum sAXL/GAS6 ratio may be a potential biomarker of pathway activation and identify patients who most benefit from Pac+AVB-500. The ORR in patients with PFI < 3 months or who had > 1 line of prior therapy were similar to those with 3-6 months PFI or ≤1 lines of therapy. Further development of AVB-500 15 mg/kg q2 weeks in combination with Pac is warranted in PROC. Clinical trial information: NCT03639246.

scholarly journals Expression and purification of the mGITR-Fc fusion protein and its effect on CD4+ T cells and dendritic cells in vitro

2015 ◽  
Vol 12 (3) ◽  
pp. 3965-3971 ◽  
Author(s):  
PEI SHEN ◽  
ZHAOLIANG SU ◽  
TING WANG ◽  
YANFANG LIU ◽  
YANG ZHAO ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Fusion Protein ◽  
Cd4 T Cells ◽  
Expression And Purification ◽  
Fc Fusion Protein

Targeting CD2 for immunotherapy: Results of a phase 1 trial with a LFA-3/IgG Fc fusion protein

1998 ◽  
Vol 16 ◽  
pp. S210
Author(s):  
Daniel Magilavy ◽  
Paul Norman ◽  
Gerard Maieau ◽  
Steven Knox ◽  
Gunther Winkler ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Phase 1 ◽  
Phase 1 Trial ◽  
Fc Fusion Protein

Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients

2012 ◽  
Vol 13 (1) ◽  
pp. 93-100 ◽  
Author(s):  
Jochen Tuettenberg ◽  
Marcel Seiz ◽  
Klaus-Michael Debatin ◽  
Wiebke Hollburg ◽  
Michael von Staden ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Healthy Volunteers ◽  
Fc Fusion Protein

Safety, pharmacokinetics, and pharmacodynamics of RSLV-132, an RNase-Fc fusion protein in systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study

Lupus ◽  
2016 ◽  
Vol 26 (8) ◽  
pp. 825-834 ◽  
Author(s):  
D J Burge ◽  
J Eisenman ◽  
K Byrnes-Blake ◽  
P Smolak ◽  
K Lau ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune System ◽  
Fusion Protein ◽  
Lupus Erythematosus ◽  
Controlled Study ◽  
Systemic Lupus ◽  
Double Blind ◽  
Extracellular Rna ◽  
Immune System Activation ◽  
Fc Fusion Protein

Blood-borne RNA circulating in association with autoantibodies is a potent stimulator of interferon production and immune system activation. RSLV-132 is a novel fully human biologic Fc fusion protein that is comprised of human RNase fused to the Fc domain of human IgG1. The drug is designed to remain in circulation and digest extracellular RNA with the aim of preventing activation of the immune system via Toll-like receptors and the interferon pathway. The present study describes the first clinical study of nuclease therapy in 32 subjects with systemic lupus erythematosus. The drug was well tolerated with a very favorable safety profile. The approximately 19-day serum half-life potentially supports once monthly dosing. There were no subjects in the study that developed anti-RSLV-132 antibodies. Decreases in B-cell activating factor correlated with decreases in disease activity in a subset of patients.

scholarly journals 438 A phase 1 trial of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, alone and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A468-A468
Author(s):  
Christine Chung ◽  
A Dimitrios Colevas ◽  
Michael Gibson ◽  
Douglas Adkins ◽  
Ammar Sukari ◽  
...  
Keyword(s):  
T Cells ◽  
Antitumor Activity ◽  
Fusion Protein ◽  
Head And Neck ◽  
Cd8 T Cells ◽  
Tumor Antigen ◽  
Cancer Center ◽  
School Of Medicine ◽  
Fc Fusion Protein ◽  
Dose Dependent

BackgroundImmuno-STATsTM are novel, modular fusion proteins designed to selectively activate tumor-antigen-specific CD8+ T cells. CUE-101 is comprised of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of a reduced affinity human interleukin-2 (IL-2) and is designed to bind and activate HPV16-specific T cells for treatment of HPV16-driven cancers. In preclinical studies CUE-101 demonstrated selective binding, activation, and expansion of HPV16 E7-specific CD8+ T cells, and a murine surrogate activated anti-tumor immunity.1MethodsCUE-101-01 is a first-in-human study in HLA-A*0201 positive patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Safety of escalating monotherapy and combination doses was evaluated to establish the recommended phase 2 dose (RP2D) for expanded enrollment. Patients with R/M HNSCC refractory to 1 or more prior platinum or pembrolizumab based systemic treatments received CUE-101 monotherapy, and patients with R/M HNSCC and PD-L1 tumor expression received combination CUE-101 and 200 mg pembrolizumab as first line treatment. Study treatment was administered intravenously every 3 weeks until progression or toxicity. Objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.ResultsAs of June 30, 2021, 39 patients have received CUE-101 monotherapy ranging from 0.06 to 8 mg/kg. The maximum tolerated dose (MTD) was not identified. Based on PK, PD and clinical data, a monotherapy RP2D of 4 mg/kg was selected. The combination cohort of 1 mg/kg CUE-101 and pembrolizumab has been tested and dose escalation is ongoing. Adverse events have included CTCAE grade 2 or less fatigue (41%), anemia (31%), lymphopenia (24%), chills (21%), decreased appetite (19%) and dyspnea (17%). CUE-101 PK data demonstrate dose-dependent increases in drug exposure that are sustained upon repeat dosing. PD data demonstrate dose-dependent expansion of HPV-16 E711-20-specific CD8+ T cells, sustained increase in natural killer cells and transient increase in Treg cells. An increase in CD3+ GZMB+ tumor infiltrating T cells was observed in tissue following treatment with CUE-101 in one patient with available pre- and post-treatment biopsies. One patient at the CUE-101 monotherapy RP2D has an ongoing partial response and 8 of 33 patients have experienced stable disease ≥ 12 weeks based on RECIST 1.1 criteria.ConclusionsCUE-101 is a novel immunotherapeutic demonstrating acceptable safety and tolerability with encouraging PD signals, supporting selective activation of tumor-specific T cells, and promising antitumor activity. Enrollment continues in both monotherapy and combination cohorts.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma.Trial RegistrationClinicalTrials.gov NCT03978689ReferencesQuayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc fusion protein, enhances tumor antigen specific T cell activation for the treatment of HPV16-driven malignancies. Clin Cancer Res 2020;26:1953–64.Ethics ApprovalThis study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB reference numbers: Advarra Pro00037736 (Moffitt Cancer Center), IRB 52744 (Stanford University School of Medicine), IRB 191714 (Vanderbilt University Medical Center Vanderbilt-Ingram Cancer Center), HRPO# 201905108 (Washington University School of Medicine), 2019–087 Karmanos Cancer Institute, DF/HCC IRB# 19-374 (Massachusetts General Hospital), WIRB 2000026098 (Yale Cancer Center), WIRB 1908869642 (University of Arizona Cancer Center), WIRB STUDY00008948 (University of Washington, Seattle), IRB(IRBMED) HUM00165746 (University of Michigan Comprehensive Cancer Center), WIRB IRB00112341(Winship Cancer Institute/Emory University), 2019–0578 (The University of Texas MD Anderson Cancer Center), IRB 20-073 (Memorial Sloan Kettering Cancer Center), IRB00255391 (Johns Hopkins University School of Medicine).

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