ERY974 / Roche - LARVOL DELTA

Organ-specific delivery of a mRNA-encoded bispecific T cell engager targeting Glypican-3 in hepatocellular carcinoma (SITC 2024) - "Background Bispecific T-cell engaging antibodies (BiTEs) have been clinically validated (e.g., blinatumomab, mosunetuzumab) but are mostly limited to hematological cancers...MTS105, at dose levels associated with a significantly lower peripheral BiTE Cmax (maximum concentration) and AUC (area under the curve), achieved a better anti-tumor efficacy than the Fc-domain-containing antibody-based BiTE (ERY974)...Conclusion The mRNA-encoded BiTE demonstrated optimal tissue/tumor-specific PK, safety and potent anti-tumor activity in preclinical models. MTS105 is currently in early human trials to assess its safety and preliminary efficacy."

Gastrointestinal Cancer • Hematological Malignancies • Hepatocellular Cancer • Oncology • Solid Tumor • GPC3

Organ-specific delivery of a mRNA-encoded bispecific T cell engager targeting Glypican-3 in hepatocellular carcinoma (SITC 2024) - "Background Bispecific T-cell engaging antibodies (BiTEs) have been clinically validated (e.g., blinatumomab, mosunetuzumab) but are mostly limited to hematological cancers...MTS105, at dose levels associated with a significantly lower peripheral BiTE Cmax (maximum concentration) and AUC (area under the curve), achieved a better anti-tumor efficacy than the Fc-domain-containing antibody-based BiTE (ERY974)...Conclusion The mRNA-encoded BiTE demonstrated optimal tissue/tumor-specific PK, safety and potent anti-tumor activity in preclinical models. MTS105 is currently in early human trials to assess its safety and preliminary efficacy."

Gastrointestinal Cancer • Hematological Malignancies • Hepatocellular Cancer • Oncology • Solid Tumor • GPC3

A Phase I Study of ERY974 in Patients With Hepatocellular Carcinoma (clinicaltrials.gov) - P1 | N=179 | Active, not recruiting | Sponsor: Chugai Pharmaceutical | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • GPC3

A Phase I Study of ERY974 in Patients With Hepatocellular Carcinoma (clinicaltrials.gov) - P1 | N=179 | Recruiting | Sponsor: Chugai Pharmaceutical | Trial completion date: Sep 2024 ➔ Dec 2025 | Trial primary completion date: Sep 2024 ➔ Dec 2025

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • GPC3

Determination of the starting dose in the first-in-human clinical trial of ERY974, a novel T cellredirecting bispecific antibody targeting glypican-3, from MABEL and NOAEL approaches (EORTC-NCI-AACR 2018) - P1; "In the cynomolgus monkey study, a transient increase in blood cytokines was observed from 1 g/kg, with IL-6 being the most prominent cytokine. Signs of a deteriorating general condition, such as red skin, reduced food consumption, and body weight loss, were also noted in a dose-dependent manner. Histopathological findings such as decreased lymphocytes in the thymus and increased immune cell infiltration in multiple tissues were also seen at the highest dose."

Clinical • P1 data • Oncology

Impact of regulatory T cells on cellular cytotoxicity induced by ERY974, a novel T cellredirecting bispecific antibody targeting glypican-3 (EORTC-NCI-AACR 2018) - P1; "These preclinical data suggest that ERY974 is unlikely to increase Tregs by CD3 stimulation, but Tregs potentially attenuate the antitumor efficacy of ERY974 against GPC3-expressing tumors. Now, the combinational effect of ERY974 and an anti-CTLA4 antibody is being further investigated in mouse syngeneic tumor models to explore the effect of a Treg-targeting agent on the antitumor activity of ERY974 against GPC3-positive cancer."

Oncology

Combining ERY974, a novel T cell-redirecting bispecific antibody targeting glypican-3, with chemotherapy profoundly improved antitumor efficacy over its monotherapy in xenograft model (AACR 2017) - P1; "In particular, ERY974 in combination with paclitaxel or cisplatin in NCI-H446 tumors caused a tumor disappearance without regrowth for a long period. These preclinical data suggest the possibility that the strategy of combining ERY974 with chemotherapy may succeed in increasing the clinical benefit. Now the combination effect is being further investigated to clarify the mechanism."

Checkpoint inhibition • Combination therapy • Monotherapy • Biosimilar • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gene Therapies • Lung Cancer • Obesity • Oncology

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. (ASCO 2017) - P1; "All patients receive premedication with dexamethasone (DEX) prior to 1st and 2nd ERY974 dose. 3 cohorts have been completed without DLT. Cohort 4 began in January 2017."

Clinical • P1 data • Biosimilar • Esophageal Cancer • Systemic Sclerosis

Combination of T cell-redirecting bispecific antibody ERY974 and chemotherapy reciprocally enhances efficacy against non-inflamed tumours. (PubMed, Nat Commun) - "Here we examine the combination effect of ERY974 and chemotherapy (paclitaxel, cisplatin, and capecitabine) in the treatment of non-inflamed tumours in a xenograft model. ERY974 increases capecitabine-induced cytotoxicity by promoting capecitabine conversion to its active form by inducing thymidine phosphorylase expression in non-inflamed MKN45 tumour through ERY974-induced IFNγ and TNFα in T cells. We show that ERY974 with chemotherapy synergistically and reciprocally increases antitumour efficacy, eradicating non-inflamed tumours."

Journal • Oncology • GPC3 • IFNG • TNFA • TYMP

Determination of starting dose of the T cell-redirecting bispecific antibody ERY974 targeting glypican-3 in first-in-human clinical trial. (PubMed, Sci Rep) - P1 | "For the phase I clinical trial, we selected 3.0 ng/kg as a starting dose, which was lower than the first-in-human dose calculated from both the no observed adverse effect level and minimal anticipated biological effect level. Combining these two methods to determine the first-in-human dose of strong immune modulators such as T cell-redirecting antibodies would be a suitable approach from safety and efficacy perspectives.Clinical trial registration: JapicCTI-194805/NCT05022927."

Journal • P1 data • Immune Modulation • Inflammation • GPC3

Priming treatment with T-cell redirecting bispecific antibody ERY974 reduced cytokine induction without losing cytotoxic activity in vitro by changing the chromatin state in T cells. (PubMed, Toxicol Appl Pharmacol) - "CD3ɛ expression, CD3-mediated signal transduction, T cell activation markers, and cytotoxicity were similar between the priming treatment with ERY974 and negative control. The present study suggests that chromatin state changes in T cells after the priming treatment was a pivotal factor in the mitigation of cytokine release after the second ERY974 treatment."

IO biomarker • Journal • Preclinical • Inflammation • Oncology • GPC3

A phase 1 dose escalation (DE) and cohort expansion (CE) study of ERY974, an anti-Glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors. (ASCO 2018) - P1; "Additional measures will be implemented to help induce CRS tolerance. The CE will utilize a 2-stage design with futility analysis and will include the following 3 arms: GPC3+ gastric/gastroesophageal junction adenocarcinoma; GPC3+ squamous esophageal cancer; and other GPC3+ tumors."

Clinical • P1 data • Esophageal Cancer

ERY974, a novel T cell-redirecting bispecific antibody targeting glypican-3, shows antitumor activity in gastric cancer patient-derived xenograft models with varying glypican-3 expression (AACR 2018) - P1; "These preclinical data support the possibility that ERY974 alone or in combination with chemotherapy will demonstrate activity in patients with gastric cancer, and the GPC3 expression profile might be a useful predictive biomarker of ERY974 efficacy for patient selection."

IO biomarker • Esophageal Cancer • Gastric Cancer

[VIRTUAL] Results of a phase 1 dose escalation study of ERY974, an anti-glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors. (AACR 2021) - "The observed responses and CRS side effects are markers of ERY974 biologic activity. At doses below 0.81 μg/kg (regimen A), ERY974 was generally well tolerated with a manageable toxicity profile, including ERY-induced CRS which was manageable with steroid administration and anti-IL6R therapy. Further research is required to determine if combined prophylactic anti-IL6R and steroid therapy is a more effective strategy for managing CRS."

Clinical • P1 data • Esophageal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CXCL8 • GPC3 • IL10

A Phase I Study of ERY974 in Patients With Hepatocellular Carcinoma (clinicaltrials.gov) - P1; N=158; Recruiting; Sponsor: Chugai Pharmaceutical

Clinical • Combination therapy • IO biomarker • New P1 trial • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • GPC3 • PD-L1

[VIRTUAL] ERY974, an Anti-Glypican 3/CD3 Bispecific T Cell-Redirecting Antibody for Treatment of Solid Tumors (PEGS 2021) - "ERY974 exerts strong anti-tumor activity against a variety of tumor models including those with a non-inflamed phenotype. In this talk, I will discuss the detailed preclinical characterization of ERY974, including the cytokine release mechanism and potential combination therapies."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • GPC3

PET imaging with the bispecific 89Zr-antibody ERY974 targeting CD3 and glypican 3 in tumor-bearing mouse models (AACR 2018) - "Spleens of huNOG mice showed CD3+ specific uptake as 89Zr-ERY974 and 89Zr-CD3xKLH uptake were higher than 89Zr-KLHxKLH uptake(P<0.05), whereas spleen uptake in NOG mice of the 3 tracers was similar. Moreover, in huNOG CD3+ mesenteric lymph nodes 89Zr-ERY974 uptake was higher than 89Zr-KLHxKLH uptake (P<0.05)CONCLUSION 89Zr-ERY974 demonstrates specific tumor uptake in NOG and huNOG mice, while in huNOG mice tumor uptake colocalized with T cell rich infiltrate and also uptake in in spleen and lymph nodes was observed."

Preclinical • Hepatocellular Cancer

Daily ascending dosing in cynomolgus monkeys to mitigate cytokine release syndrome induced by ERY22, surrogate for T-cell redirecting bispecific antibody ERY974 for cancer immunotherapy. (PubMed, Toxicol Appl Pharmacol) - "Peak cytokine levels following the single and ascending doses were 60,095 pg/mL and 1221 pg/mL for IL-6; 353 pg/mL and 14 pg/mL for TNF-α; 123 pg/mL and 16 pg/mL for IFN-γ; and 2219 pg/mL and 42 pg/mL for IL-2. The tolerance acquired with daily ascending doses up to 1000 μg/kg remained in effect for the following weekly doses of 1000 μg/kg."

Journal • Oncology

In vitro toxicological support to establish specification limit for anti-CD3 monospecific impurity in a bispecific T cell engager drug, ERY974. (PubMed, Toxicol In Vitro) - "This suggests that specification limit should be decided for each type of anti-CD3 impurity that affects T cell-activating BiAb drug products. In vitro cytokine assays can provide useful information for determining these specification limits."

Journal • Preclinical • Oncology • GPC3

Preclinical PET imaging of bispecific antibody ERY974 targeting CD3 and glypican 3 reveals that tumor uptake correlates to T cell infiltrate. (PubMed, J Immunother Cancer) - "Zr-N-suc-Df-ERY974 can potentially be used to study ERY974 biodistribution in patients to support drug development."

IO Biomarker • Journal • Preclinical • GPC3

Engineering a bispecific antibody with a common light chain: Identification and optimization of an anti-CD3 epsilon and anti-GPC3 bispecific antibody, ERY974. (PubMed, Methods) - "This format includes one of Chugai's proprietary technologies, termed ART-Ig technology, which consists of a method to identify a common light chain, isoelectric point (pI) engineering to purify the desired bispecific IgG antibody from byproducts, and Fc heterodimerization by an electrostatic steering effect. Furthermore, we describe some tips for de-risking the antibody when engineering a T cell redirecting antibody."

Journal

A Study of ERY974 in Patient With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=29; Completed; Sponsor: Chugai Pharmaceutical; Active, not recruiting ➔ Completed; Trial completion date: Dec 2019 ➔ Aug 2019; Trial primary completion date: Dec 2019 ➔ Aug 2019

Clinical • Trial completion • Trial completion date • Trial primary completion date

Differential exhaustion on cytokine release (DECREASE) by ERY974, a novel T-cell-redirecting antibody targeting glypican-3: A new type of T-cell exhaustion (AACR 2019) - "The CD19-targeting bispecific T cell engager, blinatumomab, has been used for the treatment of blood cancers, and CEA-TCB and IMCgp100 have shown promising clinical efficacy in solid tumors as well. Cytokine production following the high-dose ERY974 treatment was mitigated by the low-dose pre-treatment in vitro and in vivo. Cytotoxic activity did not decrease in this setting, thus demonstrating that the pre-treatment selectively suppressed only cytokine production. It is well known that repeated stimulation of TCR leads to T-cell exhaustion."

IO Biomarker

A Study of ERY974 in Patient With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=29; Active, not recruiting; Sponsor: Chugai Pharmaceutical; Suspended ➔ Active, not recruiting; N=125 ➔ 29

Clinical • Enrollment change • Enrollment closed