scholarly journals EXTH-09. FIRST-IN-HUMAN DOSING CONSIDERATIONS OF A BISPECIFIC ANTIBODY FOR TREATING GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi84-vi84
Author(s):  
Teilo Schaller ◽  
Matthew Foster ◽  
Ivan Spasojevic ◽  
Patrick Gedeon ◽  
Luis Sanchez-Perez ◽  
...  
Keyword(s):  
T Cells ◽  
Half Life ◽  
Bispecific Antibody ◽  
Drug Product ◽  
Phase 1 ◽  
Current Therapy ◽  
Pharmacokinetic Analysis ◽  
Specific Cell ◽  
Term Survival ◽  
Starting Dose

Abstract Current therapy for glioblastoma (GBM) is incapacitating and limited by non-specific toxicity to the surrounding brain. We have developed an immunotherapeutic approach that selectively targets GBM by redirecting the patients’ own T cells towards the tumor in an antigen-specific manner using a bispecific antibody. Our novel bispecific antibody (“BRITE”) binds GBM-specific surface marker EGFRvIII and the CD3 receptor on T cells, resulting in crosslinking and tumor-specific cell lysis. We previously showed in patient-derived and syngeneic murine glioma models, that treatment with BRITE leads to long-term survival in mice with glioblastoma. A pharmacokinetic analysis in a CD3 humanized mouse revealed that BRITE in plasma and whole blood has an initial half-life of ~8 minutes and a terminal half-life of ~2.5 hours. Given our preclinical success, we have initiated clinical trial-enabling studies, including studies of BRITE toxicology and GMP manufacturing of drug product. A crucial consideration for our proposed Phase 1 dose escalation trial is the starting dose in humans. To this end, we utilized the FDA-recommended minimum anticipated biological effect level (MABEL) of BRITE – a holistic approach that considers all available in vitro and in vivo data – to calculate the first-in-human starting dose of BRITE.

Preclinical evaluation of AMG 160, a next-generation bispecific T cell engager (BiTE) targeting the prostate-specific membrane antigen PSMA for metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 301-301 ◽  
Author(s):  
Julie Bailis ◽  
Petra Deegen ◽  
Oliver Thomas ◽  
Pamela Bogner ◽  
Joachim Wahl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Half Life ◽  
Cell Activation ◽  
Phase 1 ◽  
Xenograft Model ◽  
Cytokine Release ◽  
Single Chain

301 Background: mCRPC is a disease of high unmet medical need, especially for patients who fail novel hormonal therapies and chemotherapy. BiTE molecules provide an off the shelf therapy that activates a patient’s own immune system and redirects T cells to kill tumor cells. The BiTE mechanism of action is distinct from other immunotherapies and may unlock immune response in mCRPC. PSMA is a compelling BiTE target that is highly expressed on PCa compared to normal tissue and has increased expression in mCRPC. Methods: AMG 160 is a fully human, half-life extended (HLE) BiTE that targets PSMA on tumor cells and CD3 on T cells. AMG 160 comprises two tandem single chain variable fragments fused to an Fc domain. Results: AMG 160 binds human and non-human primate (NHP) PSMA and CD3, leading to T cell activation and proliferation and cytokine production. AMG 160 redirects T cells to kill PSMA-positive cancer cell lines in vitro, including those with low PSMA levels or androgen-independent signaling. Weekly dosing of AMG 160 induces significant antitumor activity in established PCa xenograft model. The pharmacokinetics (PK) and pharmacodynamics of AMG 160 were tested in NHP. AMG 160 treatment led to BiTE target engagement in vivo, including transient T cell activation and cytokine release in blood, and mixed cellular infiltrates in multiple organs known to express PSMA. AMG 160 treatment was well tolerated. Cytokine release associated with the first dose could be attenuated using a step dose regimen. The half-life of AMG 160 in NHP was about one week. Based on allometric scaling, the PK profile of AMG 160 may be projected to enable dosing every other week in humans. Conclusions: AMG 160 is a potent HLE BiTE with specificity for PSMA-positive tumor cells. A Phase 1 study is planned to evaluate the safety and efficacy of AMG 160 in patients with mCRPC.

scholarly journals A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects

Blood ◽  
2016 ◽  
Vol 127 (13) ◽  
pp. 1633-1641 ◽  
Author(s):  
Naoki Uchida ◽  
Takehiko Sambe ◽  
Koichiro Yoneyama ◽  
Naoki Fukazawa ◽  
Takehiko Kawanishi ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Healthy Subjects ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Procoagulant Activity ◽  
Phase 1 Study ◽  
Key Points ◽  
White Adults

Key Points Single subcutaneous dosing of ACE910 has a linear PK profile, a half-life of 4 to 5 weeks, and FVIII-mimetic procoagulant activity in humans. ACE910 at doses up to 1 mg/kg is well tolerated and has no notable adverse hypercoagulable effect in healthy Japanese and white adults.

715 FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, induces LAG-3 shedding resulting in receptor downregulation by T cells via a novel mechanism of action

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A757-A757
Author(s):  
Michelle Morrow ◽  
Mustapha Faroudi ◽  
Krishnendu Chakraborty ◽  
Wenjia Liao ◽  
Julia Winnewisser ◽  
...  
Keyword(s):  
Cell Culture ◽  
T Cells ◽  
T Cell ◽  
Mechanism Of Action ◽  
Culture Medium ◽  
Bispecific Antibody ◽  
Ex Vivo ◽  
Phase 1 ◽  
Cell Culture Medium ◽  
Antibody Targeting

BackgroundUpregulation of immune checkpoints, such as LAG-3, plays an important role in promoting resistance to anti-PD-(L)1 therapy. FS118, currently being evaluated in a Phase 1 clinical trial in patients with advanced malignancies, is a tetravalent bispecific antibody targeting LAG-3 and PD-L1 that can overcome immune suppressive signals with greater preclinical activity than a combination of monoclonal antibodies.1 Here, we demonstrate a novel mechanism of action for FS118 in shedding of LAG-3 from the surface of T cells that is not observed with the combination of PD-L1 and LAG-3 antibodies.MethodsHuman ex vivo assays were performed by co-culturing activated CD4+ T cells with iDCs in the presence of Staphylococcal enterotoxin B and FS118, or control reagents. Soluble LAG-3 was measured by ELISA from day 4 to 13. A mouse tumor model used MC38 cells implanted subcutaneously into C57Bl/6 mice. Expression of surface markers was measured on tumor-infiltrating lymphocytes (TILs) from disaggregated tumors and soluble LAG-3 was measured in serum following dosing of mice intraperitoneally with FS118 surrogate or control reagents. Soluble LAG-3 in the serum of patients treated with FS118 was measured by ELISA (Phase 1 trial NCT03440437).ResultsIn an ex vivo T cell assay, FS118 resulted in an increase in the concentration of soluble LAG-3 in the cell culture medium, an effect that was greater than with the combination of the individual bispecific components. Addition of inhibitors of either ADAM10 or ADAM17 to the FS118-treated cells resulted in a decrease in the levels of soluble LAG-3 in the cell culture medium. In MC38 tumor-bearing mice, a mouse surrogate of FS118 decreased the levels of surface LAG-3 expressed by TILs, in contrast to the combination of the bispecific components where an increase in surface LAG-3 was observed. This corresponded with an increase in soluble LAG-3 in the serum following treatment with a mouse surrogate of FS118. Finally, in patients receiving treatment with FS118, a dose dependent increase in soluble LAG-3 was detected in the blood.ConclusionsFS118 mediates LAG-3 shedding from the surface of immune cells via a mechanism that is dependent upon simultaneous binding to both PD-L1 and LAG-3. This shedding was mediated by ADAM10 and ADAM17 metalloproteinases. Removing LAG-3 from the surface of TILs via shedding may be an important mechanism by which FS118 overcomes compensatory upregulation of LAG-3 induced by PD-L1 blockade. Soluble LAG-3 may be an important biomarker for monitoring the pharmacodynamic activity of FS118 in patients.Ethics ApprovalAll animal experiments were conducted under a UK Home Office Project Licence and approved by an Animal Welfare and Ethical Review Board (AWERB) in accordance with the UK Animal (Scientific Procedures) Act 1986 and with EU Directive EU 86/609ReferenceKraman M, Faroudi M, Allen N, Kmiecik K, Gliddon D, Seal C, Koers A, Wydro M, Winnewisser J, Young L, Tuna M, Doody J, Morrow M, Brewis N. FS118, a Bispecific Antibody Targeting LAG-3 and PD-L1, Enhances T-Cell Activation Resulting in Potent Antitumor Activity. Clin Cancer Res 2020;26:3333–3344

scholarly journals Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA

2022 ◽  
Vol 11 ◽  
Author(s):  
Justin Watts ◽  
Tara L. Lin ◽  
Alice Mims ◽  
Prapti Patel ◽  
Cynthia Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Bispecific Antibody ◽  
Cytotoxic T Cells ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Dose Escalation Study ◽  
Post Hoc ◽  
Dose Levels

APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients’ T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.

scholarly journals Bi-specific Antibody Y111, Targeting PD-L1 and CD3 Considerably Enhances the Therapeutic Efficacy of Adoptive Transferred Vγ2Vδ2 T Cells

2020 ◽  
Author(s):  
Rui Yang ◽  
Susu Shen ◽  
Cheng Gong ◽  
Xin Wang ◽  
Fang Luo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Therapeutic Efficacy ◽  
Bispecific Antibody ◽  
Intracellular Cytokine Staining ◽  
T Cell Subsets ◽  
Current Therapy ◽  
Vγ2vδ2 T Cells

Abstract Background: Anti-cancer immunotherapy based on the adoptive transfer of Vγ2Vδ2 T cells has benefited to some patients in clinical trials, but the overall responses are inconsistent. Therefore, new strategies are urgently needed to improve the current therapy.Methods: In this study, a designed bispecific antibody Y111, which binds to both CD3 and PD-L1, is applied to optimally potentiate Vγ2Vδ2 T cell-based killing of cancer cells. The binding activities of Y111 was determined by Flow cytometry. CFSE/PI-based flow cytometry was applied to check the re-directed killing ability induced by Y111 in the condition of using T cell subsets, or expanded- and purified- Vγ2Vδ2 T cells as effector cells. Moreover, expanded- and purified- Vγ2Vδ2 T cells were co-cultured with tumor cells in the presence/absence of Y111 to assess the activation, degranulation, and cytokine production by intracellular cytokine staining, and CBA method. Finally, NPG-based subcutaneous tumor mouse models were used to check the in vivo therapeutic efficacy of the combination of transfused Vγ2Vδ2 T cells and Y111.Results: Due to its binding activities, Y111 apparently prompts fresh αβ-mediated lysis of tumor cell line H358 cells, but spare the effect on the fresh enriched Vγ2Vδ2 T cells from the same donors. However, Y111 increases cytotoxicity of expanded and purified Vγ2Vδ2 T cells against various NSCLC-derived tumor cell lines in a tumor cell dependent fashion. Y111 also prompted the releases of granzyme B, IFNγ and TNFα. Supporting to these observations in vitro, a combination of adoptive transferring Vγ2Vδ2 T cell and Y111 into the tumor-bearing NPG mice inhibited the growth of the established tumors in the mice.Conclusions: Taken together, our data suggest clinical potential for adoptive transferring the bispecific antibody-armored Vγ2Vδ2 T cells to treat solid tumors, such as NSCLC.

scholarly journals Development of IL-15/IL-15Rα sushi domain-IgG4 Fc complexes in Pichia pastoris with potent activities and prolonged half-lives

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Huan Xu ◽  
Mingyang Shi ◽  
Changsheng Shao ◽  
Hao Li ◽  
Jing Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Pichia Pastoris ◽  
Nk Cells ◽  
T Cell Activation ◽  
Half Life ◽  
Mammalian Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Nkt Cells ◽  
Pharmacokinetic Analysis

Abstract Background Interleukin-15 (IL-15) is a critical cytokine for the development, proliferation, and function of natural killer (NK) cells, NKT cells, and CD8+ memory T cells and has become one of the most promising protein molecules for the treatment of cancer and viral diseases. However, there are several limitations in applying IL-15 in therapy, such as its low yield in vitro, limited potency, and short half-life in vivo. To date, there are several recombinant IL-15 agonists based on configurational modifications that are being pursued in the treatment of cancer, such as ALT-803, which are mainly produced from mammalian cells. Results In this study, we designed two different forms of the IL-15 complex, which were formed by the noncovalent assembly of IL-15 with dimeric or monomeric sushi domain of IL-15 receptor α (SuIL-15Rα)-IgG4 Fc fusion protein and designated IL-15/SuIL-15Rα-dFc and IL-15/SuIL-15Rα-mFc, respectively. The two IL-15 complexes were expressed in Pichia pastoris (P. pastoris), and their activities and half-lives were evaluated and compared. Pharmacokinetic analysis showed that IL-15/SuIL-15Rα-dFc had a half-life of 14.26 h while IL-15/SuIL-15Rα-mFc had a half-life of 9.16 h in mice, which were much longer than the 0.7-h half-life of commercial recombinant human IL-15 (rhIL-15). Treatment of mice with intravenous injection of the two IL-15 complexes resulted in significant increases in NK cells, NKT cells, and memory CD8+ T cells, which were not observed after rhIL-15 treatment. Treatment of human peripheral blood mononuclear cells (PBMCs) from healthy donors with the two IL-15 complexes yielded enhanced NK and CD8+ T cell activation and proliferation, which was comparable to the effect of rhIL-15. Conclusions These findings indicate that the IL-15/SuIL-15Rα-dFc and IL-15/SuIL-15Rα-mFc produced in P. pastoris exhibit potent activities and prolonged half-lives and may serve as superagonists for immunotherapy in further research and applications.

Novel Scaffolds for Leishmania infantum Trypanothione Reductase Inhibitors Derived from Brazilian Natural Products Biodiversity

2021 ◽  
Vol 18 (4) ◽  
pp. 398-418
Author(s):  
Vinícius Guimarães da Paixão ◽  
Samuel Silva da Rocha Pita
Keyword(s):  
Natural Products ◽  
Leishmania Infantum ◽  
In Vitro Assays ◽  
Current Therapy ◽  
Pharmacokinetic Analysis ◽  
Trypanothione Reductase ◽  
Resistant Species ◽  
Reductase Inhibitors ◽  
Thiol Redox

Background: Leishmania infantum causes the most lethal form of Leishmaniasis: Visceral leishmaniasis. Current therapy for this disease is related to the development of drug-resistant species and toxicity. Trypanothione Reductase (LiTR), a validated target for the drug discovery process, is involved with parasites' thiol-redox metabolism. Objective: In this study, through Virtual Screening employing two distinct Natural Products Brazilian databases, we aimed to identify novel inhibitor scaffolds against LiTR. Results: Thus, the “top 10” LiTR-ligand energies have been selected and their interaction profiles into LiTR sites through the AuPosSOM server have been verified. Finally, Pred-hERG, Aggregator Advisor, FAF-DRUGS, pkCSM and DataWarrior were employed and their results allowed us to evaluate, respectively, the cardiotoxicity, aggregation capacity, presence of false-positive compounds (PAINS) and their toxicities. Conclusion: Three molecules that overcame the in silico pharmacokinetic analysis and have a good interaction with LiTR, were chosen to use in vitro assays hoping that our computational results reported here would aid the development of new anti-leishmanial compounds.

scholarly journals The Worm-Specific Immune Response in Multiple Sclerosis Patients Receiving Controlled Trichuris suis Ova Immunotherapy

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 101
Author(s):  
Ivet A. Yordanova ◽  
Friederike Ebner ◽  
Axel Ronald Schulz ◽  
Svenja Steinfelder ◽  
Berit Rosche ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Clinical Efficacy ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Th2 Cells ◽  
Continuous Increase ◽  
Trichuris Suis ◽  
Multiple Sclerosis Patients

Considering their potent immunomodulatory properties, therapeutic applications of Trichuris suis ova (TSO) are studied as potential alternative treatment of autoimmune disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), or inflammatory bowel disease (IBD). Clinical phase 1 and 2 studies have demonstrated TSO treatment to be safe and well tolerated in MS patients, however, they reported only modest clinical efficacy. We therefore addressed the cellular and humoral immune responses directed against parasite antigens in individual MS patients receiving controlled TSO treatment (2500 TSO p.o. every 2 weeks for 12 month). Peripheral blood mononuclear cells (PBMC) of MS patients treated with TSO (n = 5) or placebo (n = 6) were analyzed. A continuous increase of serum IgG and IgE antibodies specific for T. suis excretory/secretory antigens was observed up to 12 months post-treatment. This was consistent with mass cytometry analysis identifying an increase of activated HLA-DRhigh plasmablast frequencies in TSO-treated patients. While stable and comparable frequencies of total CD4+ and CD8+ T cells were detected in placebo and TSO-treated patients over time, we observed an increase of activated HLA-DR+CD4+ T cells in TSO-treated patients only. Frequencies of Gata3+ Th2 cells and Th1/Th2 ratios remained stable during TSO treatment, while Foxp3+ Treg frequencies varied greatly between individuals. Using a T. suis antigen-specific T cell expansion assay, we also detected patient-to-patient variation of antigen-specific T cell recall responses and cytokine production. In summary, MS patients receiving TSO treatment established a T. suis-specific T- and B-cell response, however, with varying degrees of T cell responses and cellular functionality across individuals, which might account for the overall miscellaneous clinical efficacy in the studied patients.

627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A663-A663
Author(s):  
Keegan Cooke ◽  
Juan Estrada ◽  
Jinghui Zhan ◽  
Jonathan Werner ◽  
Fei Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mouse Models ◽  
T Cell Activation ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Human T Cells

BackgroundNeuroendocrine tumors (NET), including small cell lung cancer (SCLC), have poor prognosis and limited therapeutic options. AMG 757 is an HLE BiTE® immune therapy designed to redirect T cell cytotoxicity to NET cells by binding to Delta-like ligand 3 (DLL3) expressed on the tumor cell surface and CD3 on T cells.MethodsWe evaluated activity of AMG 757 in NET cells in vitro and in mouse models of neuroendocrine cancer in vivo. In vitro, co-cultures of NET cells and human T cells were treated with AMG 757 in a concentration range and T cell activation, cytokine production, and tumor cell killing were assessed. In vivo, AMG 757 antitumor efficacy was evaluated in xenograft NET and in orthotopic models designed to mimic primary and metastatic SCLC lesions. NSG mice bearing established NET were administered human T cells and then treated once weekly with AMG 757 or control HLE BiTE molecule; tumor growth inhibition was assessed. Pharmacodynamic effects of AMG 757 in tumors were also evaluated in SCLC models following a single administration of human T cells and AMG 757 or control HLE BiTE molecule.ResultsAMG 757 induced T cell activation, cytokine production, and potent T cell redirected killing of DLL3-expressing SCLC, neuroendocrine prostate cancer, and other DLL3-expressing NET cell lines in vitro. AMG 757-mediated redirected lysis was specific for DLL3-expressing cells. In patient-derived xenograft and orthotopic models of SCLC, single-dose AMG 757 effectively engaged human T cells administered systemically, leading to a significant increase in the number of human CD4+ and CD8+ T cells in primary and metastatic tumor lesions. Weekly administration of AMG 757 induced significant tumor growth inhibition of SCLC (figure 1) and other NET, including complete regression of established tumors and clearance of metastatic lesions. These findings warranted evaluation of AMG 757 (NCT03319940); the phase 1 study includes dose exploration (monotherapy and in combination with pembrolizumab) and dose expansion (monotherapy) in patients with SCLC (figure 2). A study of AMG 757 in patients with neuroendocrine prostate cancer is under development based on emerging data from the ongoing phase 1 study.Abstract 627 Figure 1AMG 757 Significantly reduced tumor growth in orthotopic SCLC mouse modelsAbstract 627 Figure 2AMG 757 Phase 1 study designConclusionsAMG 757 engages and activates T cells to kill DLL3-expressing SCLC and other NET cells in vitro and induces significant antitumor activity against established xenograft tumors in mouse models. These preclinical data support evaluation of AMG 757 in clinical studies of patients with NET.Ethics ApprovalAll in vivo work was conducted under IACUC-approved protocol #2009-00046.

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