imgatuzumab (RO5083945) / Roche, Centessa - LARVOL DELTA

Improving dual targeting selectivity in T-cell engagers via synapse-gated and affinity-tuned trispecific antibody design. (PubMed, MAbs) - "Using an anti-receptor tyrosine kinase-like orphan receptor 1 (ROR1) mAb as a proof-of-concept anchoring arm and an array of affinity-modulated variants of the anti-epidermal growth factor receptor (EGFR) GA201 mAb as active arms, we show in vitro conditional engagement and elimination of double-positive human NCI-H358 non-small cell lung cancer cells over single-positive, non-target NCI-H358.ROR1.KO cells by affinity-modulated TriMab TCEs...Lastly, we demonstrate that the TriMab modality exhibits a favorable developability profile and mAb-like pharmacokinetic properties in human neonatal Fc receptor transgenic mice. Overall, this work presents a generalizable approach to utilizing the TriMab modality by leveraging avidity effects and molecular geometry to achieve conditional AND-gated dual TAA-targeting with a significantly improved TI."

Journal • Hematological Disorders • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • ROR1

The GATA-like transcription factor Gat201 determines alkaline-restricted growth in Cryptococcus neoformans. (PubMed, mSphere) - "In this work, we explore how Cryptococcus adapts to shifting environments and identify that the transcription factor Gat201, known to regulate capsule production, negatively regulates proliferation under alkaline conditions. Our findings highlight the need for improved understanding of proliferation/adaptation and its regulation in non-model systems."

Journal • CNS Disorders • Infectious Disease

The I-PACE study: Imgatuzumab in PAtients with advanCEd cutaneous squamous cell carcinoma (aCSCC) (ESMO 2022) - No abstract available

Clinical • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

Unraveling Capsule Biosynthesis and Signaling Networks in Cryptococcus neoformans. (PubMed, Microbiol Spectr) - "Genome-wide transcriptome profiling revealed that Bzp4, Gat201, and Ada2 promote capsule production and attachment by positively and negatively regulating genes involved in capsule synthesis and chitin/chitosan synthesis, respectively. Thus, this study provides comprehensive insights into the complex capsule-regulating signaling pathway in C. neoformans."

Journal • CNS Disorders • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • ERN1 • YAP1

I-PACE: Imgatuzumab in Patients With Advanced Cutaneous Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Pega-One S.A.S. | N=87 ➔ 0 | Trial completion date: Dec 2023 ➔ Aug 2022 | Suspended ➔ Withdrawn | Trial primary completion date: Dec 2023 ➔ Aug 2022

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

Structured Analysis Of Host-derived Cues For The Regulation Of Pathogenicity-associated Transcription Factors In Cryptococcus Neoformans (ASM Microbe 2022) - "On the other hand, the expression of FZC30, GAT201, PDR802, BZP4, MLN1, and STB4 was highly induced by glucose starvation, whereas PDR802, ZNF2, SRE1, HLH1, STB4, FZC39, FZC30, BZP4, and MLN1 was highly induced by nitrogen starvation...Supporting this, deletion of MLN1 caused growth defects supplemented with maltose or ammonium sulfate in a nutrient starvation medium. In conclusion, we systematically dissected host-signaling cues that affect in vivo expression of pathogenicity-related TFs, providing further insight into complex signaling pathways modulating the host-pathogen interactions of C. neoformans."

CNS Disorders • Infectious Disease

I-PACE: Imgatuzumab in Patients With Advanced Cutaneous Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=87 | Suspended | Sponsor: Pega-One S.A.S. | Recruiting ➔ Suspended

Trial suspension • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

I-PACE: Imgatuzumab in Patients With Advanced Cutaneous Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=87 | Recruiting | Sponsor: Pega-One S.A.S. | Not yet recruiting ➔ Recruiting

Enrollment open • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

Centessa Pharmaceuticals Announces Third Quarter 2021 Financial Results and Business Updates (GlobeNewswire) - "Pega-One’s imgatuzumab, a non-fucosylated anti-epidermal growth factor receptor ('EGFR') monoclonal antibody ('mAb') for Advanced Cutaneous Squamous Cell Carcinoma ('CSCC'): The Company expects to initiate an open-label, single arm, Phase 2 trial of imgatuzumab in advanced CSCC by the end of 2021 and dose the first subject in 1Q 2022; Janpix Limited’s dual degrader of Signal Transducer and Activator of Transcription proteins 3 and 5 ('STAT3' and 'STAT5') for Acute Myeloid Leukemia: By the end of 2021, the Company expects to select a candidate for the STAT3/5 program; PearlRiver Bio’s small molecule kinase inhibitors for EGFR mutations in Non-Small Cell Lung Cancer ('NSCLC'): The Company is progressing an EGFR-C797S mutation inhibitor for the treatment of NSCLC and expects to report on ongoing candidate selection in 2022. The Company will not select a candidate for its exon20 mutation program in 2021 and is presently reviewing this program."

Clinical • EGFR exon 20 • New P2 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

Centessa Pharmaceuticals Announces Second Quarter 2021 Financial Results and Business Updates (GlobeNewswire) - “Phase 2 trial initiation with Pega-One’s imgatuzumab in advanced cutaneous squamous cell carcinoma (CSCC): The Company expects to initiate an open label, single arm, Phase 2 trial of imgatuzumab in advanced CSCC by the end of 2021.”

New P2 trial • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

I-PACE: Imgatuzumab in Patients With Advanced Cutaneous Squamous Cell Carcinoma (clinicaltrials.gov) - P2; N=87; Not yet recruiting; Sponsor: Pega-One S.A.S.

New P2 trial • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

[VIRTUAL] Systematic Profiling of Host-derived Cues for the Regulation of Pathogenicity-related Transcription Factors in Cryptococcus neoformans (WMF 2021) - "Here we focused on 12 transcription factors, including PDR802, BZP4, HOB5, ZNF2, FZC39, FZC30, SRE1, HLH1, STB4, MLN1, MET32, and GAT201 of which in vivo expression were highly induced during host infection but did not exhibit evident in vitro phenotypes...To further investigate the gene interaction, we constructed the double knockout mutants of body temperature, carbon starvation, and nitrogen starvation. In conclusion, we provided insight into complex signaling pathways modulating the pathogenicity of C. neoformans."

CNS Disorders • Infectious Disease

[VIRTUAL] Selective and broad anti-tumor activity of AKR1C3-activated prodrug AST-3424/OBI-3424 (AACR 2021) - "The excellent anti-tumor efficacy of 3424 was further demonstrated in PDX models that have high level of AKR1C3 expression (pancreatic PA1280, gastric GA6201, Lung cancer LU2505) but not in model with low level of AKR1C3 expression (lung cancer LU2057). In the combination therapy, we have showed that 3424 could enhance the efficacy of the standard care of chemotherapy in the CDX models of VCaP CRPC, SNU-16 gastric, and A498 renal cell carcinoma. In conclusion, the results described here highlight that 3424 exhibits AKR1C3-dependent cytotoxicity in vitro and anti-tumor activity in vivo in a wide range of human cancer types, which support further development of 3424 as an anti-cancer agent for treating different types of cancer and the use of AKR1C3 as a biomarker to profile cancer patients and further guide patient selection for therapy with 3424."

Gastric Cancer • Genito-urinary Cancer • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • AKR1C3

The GAIN-C study (BP25438): Randomized phase II trial of RG7160 (GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI alone in second-line KRAS wild type (WT) or mutant metastatic colorectal cancer (mCRC) (ASCO 2012) - Presentation Time: Monday June 4, 8:00 AM to 12:00 PM; P2, N=160; Primary objective is progression free survival; secondary endpoints are to define objective response rates, the safety profile, pharmacokinetics and pharmacodynamics; A comprehensive biomarker program (blood and tumor), mainly immune-phenotyping, immunohistochemistry in tumor samples (Ventana) and immune functional tests (including adaptive responses) were set up to investigate potential predictive biomarkers and the mode of action of GA201

P2 trial update • Oncology

Exploratory pharmacodynamics (PD) trial to investigate the mechanism of action of RG7160 (GA201), a novel dual-acting, monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), compared with cetuximab (C) in neoadjuvan (ASCO 2012) - Presentation time: Sat, Jun 2; 8:00 AM - 12:00 PM; Anticipated presentation at ASCO 2012

Anticipated data presentation • Oncology

Differential effects of GA201 and cetuximab on EGFR expression and endosomal recycling in non-small cell lung cancer cell lines (AACR 2014) - Presentation time: Tuesday, Apr 08, 2014, 1:00 PM - 5:00 PM; Abstract #4511; “When combined, most of the internalized GA201 and cetuximab colocalized with the lysosomes, and were almost absent in early endosomes and recycling endosomes. Moreover, the combination efficiently inhibited EGF-induced phosphorylation of downstream signaling molecules." 

Preclinical • Biosimilar • Non Small Cell Lung Cancer • Oncology

Combination with the novel tumor-targeted CEA-IL2v immunocytokine enhances the activity of ADCC-competent and glycoengineered antibodies in vitro and in vivo (AACR 2014) - Presentation time: Monday, Apr 07, 2014, 1:00 PM - 5:00 PM; Abstract #2579; "Addition of trastuzumab or cetuximab resulted in induction of activation markers and enhanced killing of tumor cells...The combination of CEA-IL2v (1 mg/kg, q7d×3) with trastuzumab (10 mg/kg in KPL4 and 25 mg/kg in N87, q7d×3) resulted in superior inhibition of tumor growth compared to the respective single-agent treatments, combination therapy induced 6/9 complete tumor remissions in N87 and 3/5 in KPL4....in the i.v. A549 NSCLC and i.s. LS174T CRC xenografts, the combination of CEA-IL2v (1 mg/kg for A549 and 2 mg/kg for LS174T, q7d×3) with GA201 (25 mg/kg, q7d×3) resulted in superior median survival compared to the respective single-agent treatments with long term survival of 10/10 animals in the A549 model and survival of 2/8 animals in the LS174T model."

Preclinical • Biosimilar • Oncology

A study of RO5083945 in combination with FOLFIRI versus FOLFIRI plus cetuximab or FOLFIRI alone as second line treatment in patients with metastatic colorectal cancer (clinicaltrials.gov) - P2, N=160; Recruiting; N= 0 -> 160

Enrollment • Colorectal Cancer • Oncology

GAIN-(L): Efficacy and biomarker findings of RG7160 (GA201), a novel, dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with first-line cisplatin and pemetrexed in metastatic nonsquam (ASCO 2012) - Presentation time: Saturday June 2, 1:15 PM to 5:15 PM; P1b, N=14; NCT01185847; There were 6 confirmed partial responses (43%, 5 in 1400 mg cohort) and 7 patients (50%) with stable disease >=9 weeks; The RP2D of GA201 in combination with chemotherapy was established to be 1400 mg

P1 data • Non Small Cell Lung Cancer • Oncology

Extracellular domain shedding influences specific tumor uptake and kinetics of EGFR PET tracer 89Zr-imgatuzumab (AACR-NCI-EORTC 2015) - Presentation time:  Friday, Nov 06, 2015, 12:15 PM - 3:15 PM; Abstract #A86; "89Zr-imgatuzumab effectively accumulates in EGFR expressing tumors. A431 tumors extensively shedded EGFR, which highly influenced 89Zr-imgatuzumab kinetics in A431 bearing mice."

Preclinical • Oncology

A study of RO5083945 in combination with chemotherapy versus chemotherapy alone in patients with advanced or recurrent non-small cell lung cancer (clinicaltrials.gov) - P2, N=90; Sponsor: Hoffmann-La Roche; Active, not recruiting; Trial completion date: Aug 2013 -> Nov 2013.

Trial completion date • Non Small Cell Lung Cancer • Oncology

A Study of RO5083945 in combination with chemotherapy versus chemotherapy alone in patients with advanced or recurrent non small cell lung cancer (clinicaltrials.gov) - P2, N=160; Not yet recruiting; Start date: NA → Nov’ 10;

Start date • None • Oncology

Role and mechanisms of resistance of epidermal growth factor receptor antagonists in the treatment of colorectal cancer. (PubMed) - "Although the negative predictive role of RAS and possibly BRAF mutations has already been established, more comprehensive efforts are needed to optimize the use of these drugs. At the same time, understanding the underlying biology will help basic scientists to develop new compounds able to overcome both primary and acquired resistance and help clinical researchers to test novel drugs within adequately designed trials whose results eventually are expected to reshape the overall treatment strategy."

Journal • Biosimilar • Colorectal Cancer • Multiple Myeloma • Oncology

Correlative biomarker analysis of sequential tumor biopsies in a ph I mode of action (MoA) study in neoadjuvant head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with RG7160 (GA201), a novel dual-acting, monoclonal antibody (mAb)... (ASCO 2013) - Presentation time: Monday, Jun 3, 8:00 AM - 11:45 AM; Abstract #3035; P1, N=NA; NCT01046266; Sponsor: Hoffmann-La Roche; "These markers were unrelated to the BL tumor EGFR and pERK expression. Strongest bivariate correlation was seen between (CD16, CD68), (CD3, 4, 8) and (CD4, NKp46). GA201 treatment induced positively correlated dynamic changes (chg) between (CD8, CD68), while C did so for (CD4, CD16) and (CD16, CD68). Strong and negative correlation between (CD56chg, PETchg) was seen only in pts treated with 1,400 mg GA201."

P1 data • Oncology

GAIN-(C): Efficacy and safety analysis of imgatuzumab (GA201), a novel dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with FOLFIRI compared to cetuximab plus FOLFIRI in second-line (ASCO-GI 2015) - Abstract #669; P2, N=169; Sponsor: Hoffmann-La Roche; NCT01326000; "Median PFS (Investigator reported) was 7.3 months in group 1 versus6.1 in group 2 (HR, 1.13; 95% CI 0.69-1.86) and 5.2 months in group 3 versus 4.3 in group 4 (HR, 0.94; 95% CI 0.57-1.54). Adverse events of ≥ grade 3 included rash (42.5%, 9.8%, 31.8%, 0% in groups 1, 2, 3 and 4 respectively), hypomagnesemia (30.0%, 4.9%, 22.7%, 0% respectively) and neutropenia (20.0%, 29.3%, 25.0%, 21.4% respectively)."

P2 data • Colorectal Cancer • Oncology