406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

A phase 1 dose-escalation study of a PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2585-2585
Author(s):  
Rachel E. Sanborn ◽  
Rodolfo Eduardo Bordoni ◽  
Gini F. Fleming ◽  
Mustafa Khasraw ◽  
Thomas Hawthorne ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Primary Study ◽  
Clinical Activity ◽  
The Impact

2585 Background: CDX-527 is a bispecific antibody (BsAb) targeting PD-L1 and CD27 that is designed to block immune checkpoint PD-L1/PD-1 interactions while providing immune costimulation through CD27 signaling. CD27 is a key immunostimulatory molecule that enhances T cell activation, effector function, and survival. Combining anti-PD-L1 and anti-CD27 mAbs synergize in preclinical studies, activating complementary cytotoxic and proliferative gene expression profiles, respectively. Clinical studies demonstrated the safety and biological activity of combining varlilumab, an agonist anti-CD27 mAb, with nivolumab or atezolizumab, along with modest clinical activity of the combinations. CDX-527 is a novel human BsAb containing a neutralizing, high affinity IgG1k PD-L1 mAb and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations. Methods: CDX527-01 is a phase 1 first-in-human, open-label, multi-center, dose-escalation (DE) and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 in patient with advanced solid tumors that have progressed on standard-of-care therapy. The primary study objective is to characterize the safety and tolerability of CDX-527. CDX-527 is administered intravenously Q2W with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The first 2 cohorts of the DE phase initiate with single patients and subsequent DE cohorts will be conducted in 3+3 manner. Tumor-specific expansion cohorts may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX-527. Tumor assessments are performed Q8W by the investigator per iRECIST. Biomarker assessments include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment in paired tumor biopsies. Results: To date, 8 patients have received CDX-527 in doses ranging from 0.03 mg/kg to 1 mg/kg and 3 are still on treatment. There has been no drug related SAEs, DLTs or discontinuations due to an AE. Most common treatment related AEs were influenza-like illness, fatigue, and arthralgia (all at 25%). All drug related AEs have been grade 1 or 2. Conclusions: Preliminary results indicate that the novel anti-PD-L1xCD27 bispecific antibody CDX-527 up to and including the 1 mg/kg dose level has been well tolerated. Additional data will be presented, including the safety profile at higher dose levels along with clinical activity, as well as PK and PD data. Clinical trial information: NCT04440943.

HPN217-3001: A Phase 1/2 Open-Label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and Pharmacokinetics of HPN217, a Bcma-Targeting T-Cell Engager, in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Henning Schade ◽  
Sumit Madan ◽  
Eva Medvedova ◽  
Rajneesh Nath ◽  
Lisa Knapp ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Ad Hoc ◽  
Phase 1 ◽  
Advisory Board ◽  
Publicly Traded ◽  
Open Label

Background B cell maturation antigen (BCMA) has emerged as a promising target for multiple myeloma (MM) therapies based on its restricted expression profile and functional role in promoting MM cell survival. Some of these BCMA targeting molecules, including CAR-T cells and CD3-based T cell engaging molecules, have demonstrated efficacy against relapsed/refractory MM (R/R MM) in clinical trials. HPN217 is a BCMA -targeting T cell engager with Harpoon's proprietary Tri-specific T cell Activating Construct (TriTAC®) platform, a recombinant polypeptide of ~50kDa containing three humanized antibody-derived binding domains, targeting BCMA (for tumor binding), albumin (for half-life extension) and CD3 (for T cell engagement). It has been engineered to be a small, globular protein to enable efficient exposure in tumor tissue with prolonged half-life and excellent stability under physiological conditions. HPN217 mediates potent target tumor cell killing in a BCMA-specific manner in vitro and in xenograft models in the presence of T cells. Consistent with its mechanism of action (MOA), tumor cell killing is accompanied by T cell activation, cytokine induction, and T cell expansion. HPN217 binds monomerically to CD3 and BCMA, minimizing non-specific T-cell activation. Study Design and Methods HPN217-3001 is an ongoing Phase 1/2, open-label, multicenter, global study of the safety, tolerability, and pharmacokinetics of HPN217 in patients with relapsed and refractory multiple myeloma. The study is divided into 2 parts: Dose Escalation (Part 1) and Expansion (Part 2). Part 1 of the study will determine the Maximum Tolerated Dose (MTD) or the recommended Phase 2 dose (RP2D); Part 2 of the trial will evaluate the safety and efficacy of HPN217 at MTD/RP2D in patients with R/R MM. Patients, who have received at least 3 prior therapies (including proteasome inhibitor, immune modulatory drug, and an anti-CD38 antibody each) and are not candidates for or intolerant to all therapies known to provide clinical benefit in MM, are eligible for enrollment. Prior exposure to a BCMA-targeting agent is permitted in Part 1 but not in Part 2. HPN217 is administered once weekly via IV infusion on Days 1, 8 and 15 during each 21-day cycle at a flat dose. Dose escalation is being performed in serial patient cohorts starting with single patient dose cohorts followed by a conventional 3 + 3 design. Intra-patient dose escalation is permitted. Dose expansion will be initiated once the MTD or a RP2D is established based on safety, preliminary efficacy, PK, and pharmacodynamic data from dose escalation, with a Simon 2-stage design to assess preliminary clinical efficacy of HPN217. Patients may continue weekly HPN217 treatment until disease progression. Primary study endpoints include frequency and severity of treatment-emergent AEs (TEAEs) graded according to NCI CTCAE version 5.0, number and severity of dose limiting toxicities (DLTs) following treatment with HPN217, and PK parameters of HPN217. The study will also evaluate overall response rate (ORR) based on IMWG response criteria, progression-free survival (PFS) and overall survival (OS), duration of response (DOR), immunogenicity of HPN217, and other exploratory endpoints related to the mechanism of action of HPN217. (NCT04184050) Disclosures Madan: Sanofi: Other: Ad hoc advisory board; GSK: Other: Ad hoc advisory board, Speakers Bureau; Karopharm: Speakers Bureau; Amgen: Other: Ad hoc advisory board, Speakers Bureau; Janssen: Other: Ad hoc advisory board, Speakers Bureau; Takeda: Other: Ad hoc advisory board, Speakers Bureau; Celgene/BMS: Other: Ad hoc advisory board, Speakers Bureau. Nath:Harpoon Therapeutics: Consultancy. Knapp:Harpoon Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lemon:Harpoon Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sun:Harpoon Therapeutics: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Dual checkpoint blockade of CD47 and PD-L1 using an affinity-tuned bispecific antibody maximizes antitumor immunity

2021 ◽  
Vol 9 (10) ◽  
pp. e003464
Author(s):  
Shih-Hsun Chen ◽  
Pawel K Dominik ◽  
Jessica Stanfield ◽  
Sheng Ding ◽  
Wenjing Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Regulatory Protein ◽  
Checkpoint Blockade ◽  
Therapeutic Window ◽  
Clinical Activity ◽  
Type I

BackgroundT cell checkpoint immunotherapies have shown promising results in the clinic, but most patients remain non-responsive. CD47-signal regulatory protein alpha (SIRPα) myeloid checkpoint blockade has shown early clinical activity in hematologic malignancies. However, CD47 expression on peripheral blood limits αCD47 antibody selectivity and thus efficacy in solid tumors.MethodsTo improve the antibody selectivity and therapeutic window, we developed a novel affinity-tuned bispecific antibody targeting CD47 and programmed death-ligand 1 (PD-L1) to antagonize both innate and adaptive immune checkpoint pathways. This PD-L1-targeted CD47 bispecific antibody was designed with potent affinity for PD-L1 and moderate affinity for CD47 to achieve preferential binding on tumor and myeloid cells expressing PD-L1 in the tumor microenvironment (TME).ResultsThe antibody design reduced binding on red blood cells and enhanced selectivity to the TME, improving the therapeutic window compared with αCD47 and its combination with αPD-L1 in syngeneic tumor models. Mechanistically, both myeloid and T cells were activated and contributed to antitumor activity of αCD47/PD-L1 bispecific antibody. Distinct from αCD47 and αPD-L1 monotherapies or combination therapies, single-cell RNA sequencing (scRNA-seq) and gene expression analysis revealed that the bispecific treatment resulted in unique innate activation, including pattern recognition receptor-mediated induction of type I interferon pathways and antigen presentation in dendritic cells and macrophage populations. Furthermore, treatment increased the Tcf7+ stem-like progenitor CD8 T cell population in the TME and promoted its differentiation to an effector-like state. Consistent with mouse data, the compounds were well tolerated and demonstrated robust myeloid and T cell activation in non-human primates (NHPs). Notably, RNA-seq analysis in NHPs provided evidence that the innate activation was mainly contributed by CD47-SIRPα but not PD-L1-PD-1 blockade from the bispecific antibody.ConclusionThese findings provide novel mechanistic insights into how myeloid and T cells can be uniquely modulated by the dual innate and adaptive checkpoint antibody and demonstrate its potential in clinical development (NCT04881045) to improve patient outcomes over current PD-(L)1 and CD47-targeted therapies.

Phase I dose escalation study of recombinant interleukin-21 (rIL-21, BMS-982470) in combination with ipilimumab (Ipi) in patients (pts) with advanced or metastatic melanoma (MM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3109-TPS3109 ◽  
Author(s):  
Shailender Bhatia ◽  
Brendan D. Curti ◽  
Michael S. Gordon ◽  
Jason Chesney ◽  
Theodore Logan ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Phase I ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Combined Treatment ◽  
Clinical Activity

TPS3109 Background: Ipilimumab is a monoclonal anti-CTLA-4 antibody that promotes T-cell activation and has been approved for the treatment of pts with advanced melanoma. The cytokine rIL-21 is a T-cell and NK-cell growth factor that has also demonstrated antitumor activity in selected solid tumors including MM. We hypothesize that coordinated stimulation of T and/or NK cell function with rIL-21 in conjunction with T-cell checkpoint inhibitor blockade with Ipi will achieve enhanced biologic and clinical activity compared to either agent alone. Here we describe an ongoing phase Ib study to investigate the clinical and biologic effects of combined treatment with rIL-21 and Ipi in pts with MM. Methods: The phase I study includes dose escalation (Part 1) using a 6 + 6 design and cohort expansion (Part 2). In Part 1 (n=48), successive cohorts of pts with melanoma will be treated with rIL-21 in combination with Ipi as follows: Arm A, rIL-21 (10, 30, or 50 μg/kg daily x 5) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle; or Arm B, rIL-21 (30, 100, or 150 μg/kg weekly) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle. In Part 1, all subjects will receive an initial cycle with rIL-21 monotherapy (lead-in) for biomarker and PK assessment that will be the same as the dose of rIL-21 specified for the cohort. Four cycles of combination treatment will follow the lead-in with restaging evaluation after 4 combination cycles. Subjects with initial benefit are eligible for retreatment at progression. In Part 2, pts (n=25/arm) will be randomly assigned to one of 3 cohorts: Ipi monotherapy at 3 mg/kg Q3W or Ipi + weekly rIL-21 or Ipi + daily rIL-21 at the MTD determined for each schedule in Part 1. The primary objectives of this study are to evaluate the safety of rIL-21 + Ipi and to define the MTD of the respective rIL-21 + Ipi regimens. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunologic effects of this combination in peripheral blood and paired tumor biopsy specimens, and the association of these effects with clinical outcome. Clinical trial information: NCT01489059.

Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9520-9520 ◽  
Author(s):  
Paolo Antonio Ascierto ◽  
Ignacio Melero ◽  
Shailender Bhatia ◽  
Petri Bono ◽  
Rachel E. Sanborn ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Escape ◽  
Phase 1 ◽  
Objective Response ◽  
Lymphocyte Activation ◽  
Clinical Activity ◽  
Tumor Immune Escape ◽  
Duration Of Response

9520 Background: Signaling via LAG-3 and other T-cell inhibitory receptors (eg, PD-1) can lead to T-cell dysfunction and tumor immune escape. Simultaneous blockade of LAG-3 + PD-1 may synergistically restore T-cell activation and enhance antitumor immunity. In a phase 1/2a study, BMS-986016 (IgG4 mAb targeting LAG-3) ± nivo (IgG4 mAb targeting PD-1) demonstrated tolerability, peripheral T-cell activation, and preliminary clinical activity (NCT01968109; Lipson E, et al. J Immunother Cancer. 2016;4[s1]:173 [P232]). Here we describe preliminary efficacy of BMS-986016 + nivo in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, along with updated safety from all dose expansion pts. Methods: Pts with MEL must have had prior anti–PD-1/PD-L1 (± anti–CTLA-4 or BRAF/MEK inhibitors) and progressive disease (PD). Pts received BMS-986016 80 mg + nivo 240 mg IV Q2W. Primary objectives were safety and objective response rate (ORR; complete [CR] + partial [PR] response), disease control rate (DCR; CR + uCR + PR + uPR + stable disease [SD] > 12 wk), and duration of response (RECIST v1.1). Results: At data cutoff, 43 pts with MEL had been treated with BMS-986016 + nivo following PD on/after prior anti–PD-1/PD-L1 with known prior best responses of 1 CR, 9 PR, 12 SD, and 16 PD. Of the 43 pts, 30 (70%) also had prior anti–CTLA-4, 20 (47%) had ≥ 3 prior therapies, and 15 (35%) had BRAFmutations .In the 31 efficacy-evaluable pts to date, ORR was 16% (confirmed/unconfirmed) and DCR was 45% with benefit observed even in some pts refractory to prior anti–PD-1. Evaluations are ongoing for most pts, with median treatment duration of 10 wk for all 43 pts. Immunopathologic (eg, PD-1/PD-L1 and LAG-3 expression) and clinical characteristics of responders vs nonresponders will be presented. Any grade and grade 3/4 treatment-related AEs occurred in 46% and 9%, respectively, across all dose expansion pts (n = 129). Conclusion: Addition of BMS-986016 to nivolumab demonstrates encouraging initial efficacy in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, and a safety profile similar to nivolumab monotherapy. Clinical trial information: NCT01968109.

PEGylated human IL-10 (AM0010) in combination with pembrolizumab in anti-PD1 and CTLA-4 refractory melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3084-3084 ◽  
Author(s):  
Aung Naing ◽  
Deborah Jean Lee Wong ◽  
Jeffrey R. Infante ◽  
Manish R. Patel ◽  
Shubham Pant ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
De Novo ◽  
Phase 1 ◽  
High Response Rate ◽  
Clinical Activity ◽  
Study Objective

3084 Background: Melanoma has a high response rate to anti-PD-1 alone. More than 50% of melanoma on anti-PD-1 progress within one year. IL-10 inhibits inflammation and stimulates the cytotoxicity and proliferation of tumor infiltrating CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are induced on activated CD8 T cells, providing a mechanistic rationale for combining AM0010 and anti-PD1. AM0010 alone has established tolerability and anti-tumor activity in a phase 1 study. Objective responses were observed in 4 of 15 pts with RCC, one patient with uveal melanoma and cutaneous T cell lymphoma, each. Methods: 25 melanoma pts who had progressed on prior anti-CTLA4 and on prior anti-PD-1 containing regimen were treated with AM0010 (20mg/kg qd, SQ) and pembrolizumab (2mg/kg, q3wk IV). Patients had a median of 3.5 prior therapies (range 2-6) and a median of 2 prior immune therapies (range 1-6). Tumor responses were monitored following irRC. Immune responses were measured by analysis of serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Results: AM0010 plus pembrolizumab was well tolerated. All treatment related adverse events (TrAE) were reversible. DLTs and SAEs leading to study discontinuation were not observed. G3/4 TrAEs were observed in 11 of 25 pts and included fatigue (8) thrombocytopenia (6), anemia (4), rash (1) and hypertriglyceridemia (1). There were no objective tumor responses. 9 of 20 evaluable pts had stable disease (DCR = 45%). As of Jan. 31 2017, the mPFS was 2.0 mo. and the mOS was not reached, with a mFU of 15.5 mos (range 10.0-18.4). AM0010 plus pembrolizumab increased Th1 cytokines as well as the number and proliferation of PD1+ Lag3+ activated CD8 T cells in the blood while reducing inflammatory cytokines and TGFb. A de-novo oligoclonal expansion of T cell clones in the blood and an increase of tumor infiltrating Granzyme+ PD1+ CD8+ T cells in tumor biopsies of treated patients was observed. Conclusions: AM0010 in combination with anti-PD1 is well-tolerated in refractory melanoma pts. The clinical activity and the observed CD8+ T cell activation may suggest to study AM0010 in combination with an anti-PD-1 in melanoma patients with less prior treatments. Clinical trial information: NCT02009449.

A phase I dose escalation (DE) and cohort expansion (CE) study of ERY974, an anti-glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3112-TPS3112
Author(s):  
Kenji Hashimoto ◽  
Ayesh Perera ◽  
Naofumi Sugaya ◽  
Yoshitaka Ogita ◽  
Mikiko Nakamura ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Gastroesophageal Junction ◽  
Occurrence Rate ◽  
Cytotoxic T Cell ◽  
Therapy Strategy

TPS3112 Background: Bispecific antibodies to facilitate T-cell directed cytotoxicity (TDCC) is a proven therapy strategy in cancer. ERY974 is a humanized IgG4 bispecific antibody designed to simultaneously bind to cytotoxic T-cell CD3 receptors and GPC3 (a glycoprotein expressed on cell surface of several tumors) to elicit T-cell activation and TDCC. The objectives of this multi-country, phase 1 study of ERY974 is to determine the maximum tolerated dose (MTD) and to perform a preliminary assessment of anti-tumor activity in patients with solid tumors expressing GPC3. Methods: ERY974 is dosed IV weekly. All patients receive premedication with dexamethasone (DEX) prior to 1st and 2nd ERY974 dose. DE uses an accelerated titration design (ATD), then a modified continual reassessment method (mCRM) described by one-parameter logistic model, to determine MTD, where DLT occurrence rate is 0.25. Combining ATD and mCRM is to permit rapid dose escalation whilst minimizing patient numbers exposed to sub-therapeutic doses, and to accurately determine MTD. Once grade 2 (G2) cytokine release syndrome (CRS) is observed, DEX is increased. If ≥G2 CRS is again observed, then at all subsequent doses the 1st dose of ERY974 is fixed at the last dose level when < G2 CRS was not seen, DE proceeds with the 2nd dose. ATD commences with n = 1, increasing to n = 3 once drug-related ≥G2 toxicity is seen. mCRM starts after 1st dose limiting toxicity (DLT), with the modifications of at least 3 patients required to dose escalate and up to 1.5x increment to minimize risk of toxicity. CE has 3 arms: GPC3+ gastric/gastroesophageal junction adenocarcinoma; GPC3+ squamous esophageal cancer; and other GPC3+ tumors. A 2-stage design is used to allow CE to stop early for futility. Subjects are adults with histologically confirmed, measurable malignant solid tumors and/or metastatic disease not amenable to standard therapy, and life expectancy ≥3 months. Patients with > 1cm or > 1 brain metastasis, current/previous interstitial lung disease, and acute/chronic infection are excluded. 3 cohorts have been completed without DLT. Cohort 4 began in January 2017. Clinical trial information: NCT02748837.

NVG-111, a novel ROR1xCD3 bispecific antibody for non-Hodgkin lymphoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7549-7549
Author(s):  
David Granger ◽  
Satyen Gohil ◽  
Alessandro Barbarulo ◽  
Annalisa Baccaro ◽  
Vincent Muczynski ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Human Study ◽  
Phase 2 ◽  
Cytokine Release ◽  
Non Hodgkin Lymphoma

7549 Background: Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a type I transmembrane protein is highly expressed on an array of haematological and solid tumours. NVG-111 is a humanised, tandem scFv ROR1xCD3 bispecific antibody previously shown to elicit potent killing of tumour cells in vitro and in vivo by engaging a membrane-proximal epitope in the Wnt5a-binding Frizzled domain of ROR1 and redirecting T cell activity. The in vitro potency and pharmacodynamic responses to NVG-111 were assessed to support progression to a first-in-human study. Methods: The potency of NVG-111 in vitro was determined by evaluating the concentration response for cytotoxicity, T cell activation, and cytokine release in co-cultured Jeko-1 and unstimulated human T cells. Comparative data were generated for the marketed CD19xCD3 bispecific antibody, blinatumomab. Potency data for NVG-111 were used together with allometric scaling from murine PK studies to inform planned clinical doses. Results: NVG-111 demonstrated T cell-dependent cytotoxicity, T cell activation and levels of cytokine release similar in potency to blinatumomab. Cytotoxic responses of both NVG-111 and blinatumomab were more potent than T cell activation and cytokine release. Dose response curves for NVG-111 showed a decrease in activity beyond the concentration of maximal response (ie “hook effect”). We hypothesise this is due to receptor saturation, inhibiting synapse formation. NVG-111 has progressed to a Phase 1/2 first-in-human study in patients with debulked, relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), the drug given as add-on to ≥2nd line therapy with a Bruton’s tyrosine kinase inhibitor, or venetoclax. Phase 1 includes escalating doses of 0.3 to 360 µg/day via continuous infusion over 3 cycles (each 21 days on, 7 days off) to establish safety, PK, pharmacodynamics (PD) and recommended phase 2 dose (RP2D). Predicted exposure at 0.3 µg/day is ̃EC20 for cytotoxicity in vitro and below the lowest EC10 for cytokine release. PD biomarkers in the study include systemic cytokines. Phase 2 will study efficacy and safety of the RP2D in CLL and MCL, with primary endpoint complete response rate; other efficacy endpoints include minimal residual disease and progression free survival. Conclusions: NVG-111 shows potent T-cell mediated lymphoma cell cytotoxicity in vitro at concentrations well below those associated with extensive cytokine release. NVG-111 is in an ongoing Phase 1/2 study and may present a novel option for adoptive immunotherapy in patients with non-Hodgkin lymphoma and potentially other cancers. Clinical trial information: 2020-000820-20. [Table: see text]

scholarly journals PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emily Lee ◽  
Sarah Szvetecz ◽  
Ryan Polli ◽  
Angelo Grauel ◽  
Jayson Chen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Standard Of Care ◽  
Tumor Growth Inhibition ◽  
High Grade ◽  
Ovarian Cancers ◽  
Late Stage Diagnosis ◽  
Anti Tumor Activity

AbstractHigh-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

398 AGEN1181, an Fc engineered anti-CTLA-4 antibody, demonstrates clinical activity, alone or in combination with balstilimab (anti-PD-1), and broadens the therapeutic potential of CTLA-4 therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A423-A423
Author(s):  
Steven O’Day ◽  
Anthony El khoueiry ◽  
Chethan Ramamurthy ◽  
Andrea Bullock ◽  
Irina Shapiro ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Models ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Control ◽  
Clinical Activity ◽  
Small Subset ◽  
Tumor Bearing Mouse ◽  
High Affinity ◽  
Tumor Bearing

BackgroundImmune checkpoint therapies targeting CTLA-4, alone, or in combination with anti-PD-1 have shown durable responses in cancer patients. However, responses are limited to a small subset of patients in the most common immunogenic cancers. Here we describe, a novel anti-CTLA-4 antibody, AGEN1181, with enhanced FcyR-dependent functionality that harnesses a novel mechanism of action to promote superior T cell activation and anti-cancer immunity. Concordant with preclinical findings, we report preliminary safety, pharmacodynamic and efficacy data from a phase 1 study of AGEN1181 (NCT03860272), alone or in combination with balstilimab (anti-PD-1 antibody) in a range of immunogenic and non-immunogenic tumors.MethodsThe functional activity of AGEN1181 or AGEN1181-like mouse surrogate were assessed in primary cell-based assays or in PD-1 refractory syngeneic tumor-bearing mouse models (B16F10 or KPC pancreatic tumor). Efficacy was evaluated as monotherapy, or in combination with anti-PD-1, focal radiation or chemotherapy. In an ongoing phase I study, AGEN1181 is administered intravenously once every 3- or 6-weeks as monotherapy (0.1–4 mg/kg), or every 6-weeks (1–4 mg/kg) in combination with balstilimab (3 mg/kg) dosed every 2 weeks. Dose-limiting toxicities were evaluated in the first 28 days of treatment. Neoantigen burden was assessed from pre-treatment tumor biopsy, as available, by next-generation sequencing. Fcγ receptor genotyping was assessed by real-time PCR. Immunophenotyping of peripheral blood mononuclear cells collected pre- and post-treatment were analyzed by flow cytometry.ResultsPreclinically, AGEN1181 demonstrated superior T cell activation than a standard IgG1 anti-CTLA-4 analogue in donors expressing either the low or high affinity FcγRIIIA. In poorly immunogenic tumor-bearing mouse models, AGEN1181-like surrogate demonstrated robust tumor control in combination with anti-PD-1 and focal radiation or chemotherapy. As of August 25th, 2020, we observed a clinical benefit rate of 63–53% at 6 and 12 weeks respectively among evaluable treated patients. We observed two durable responses in patients with endometrial cancer that were BRCA-, microsatellite stable and PD-L1 negative. These patients progressed on prior PD-1 therapy or chemoradiation respectively. Notably, responders expressed either the low or high affinity FcγRIIIA. AGEN1181 showed potent dose-dependent increases in peripheral CD4+Ki67+, CD4+ICOS+ and CD4+HLA-DR+ T-cells. Treatment was well tolerated through the highest dose tested. Grade 3 or greater immune-related adverse events occurred in 28.5% patients and were consistent with CTLA-4 therapies.ConclusionsAGEN1181 is designed to expand the benefit of anti-CTLA-4 therapy to a broader patient population. AGEN1181, alone or in combination with balstilimab, demonstrates clinical activity in heavily pretreated patients.Trial RegistrationNCT03860272

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