In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 32-32
Abstract:
Background. Colorectal cancer (CRC) is the third most common cancer and remains a large unmet need. Dysregulation of Wnt and receptor tyrosine kinase (RTK) signalling pathways are important oncogenic driving events in CRC. Due to this dysregulation, Wnt target genes are expressed at higher levels in CRC particularly in tumor initiating cells. We previously performed an unbiased screen of bispecific antibodies (bAbs) targeting Wnt and RTK targets that resulted in the selection of MCLA-158. Methods. A cohort of 32 genetically and transcriptionally annotated patient-derived colorectal cancer and normal colon organoids were used to functionally characterize responses to antibodies based on morphological changes with high content 3D imaging. Binding affinity was measured by surface plasma resonance and cell based assays. The antibody binding epitopes were mapped by shotgun mutagenesis and FACS based screening. Ligand (R-spondin or EGF) blocking activity was measured in vitro by competition for ligand binding or functional inhibition of ligand dependent growth. In vivo activity was evaluated in xenograft models generated from organoids subcutaneously implanted into immunocompromised mice. Safety was evaluated via once weekly intravenous administration of MCLA-158 to cynomolgus monkeys for 4 weeks and monitoring for pathological changes. Results. MCLA-158, an ADCC enhanced common light chain IgG1 bispecific antibody, binds in domain III of EGFR and in the N-Cap/1st LRR of LGR5, both ligand binding regions, however, only EGF binding was blocked by MCLA-158. MCLA-158 demonstrated inhibitory activity in 74% of tumor organoids independent of KRAS mutational status but was not active on organoids of the cohort harboring both KRAS and PIK3CA mutations. MCLA-158 was significantly more active on organoids derived from tumors than from normal tissue in contrast to cetuximab, which demonstrated equivalent activity on both (range 20-100 fold, n=4). In vivo activity was evaluated against tumor organoids with different KRAS mutation status shown to be sensitive to MCLA-158 in vitro. In all cases, MCLA-158 significantly inhibited the growth of the tumor compared to both control and cetuximab treatment. Inhibitors of both the Wnt and EGFR pathways have shown significant toxicity in humans. An initial evaluation of MCLA-158 toxicity in cynomolgus monkeys did not demonstrate any pathological finding after repeated dosing at 25mg/kg. Conclusions. MCLA-158 demonstrates superior activity compared to reference antibodies in both in vitro and in vivo tumor organoid based assays regardless of KRAS status and was well tolerated in non-human primates. These preclinical data suggest MCLA-158 could benefit patients with metastatic CRC and warrant clinical evaluation. Citation Format: Rob Roovers, Bram Herpers, Mark James, Berina Eppink, Carme Cortina, David Maussang-Detaille, Ingrid Kolfschoten, Sylvia Boy, Marc van de Wetering, Wim De Lau, Robert Doornbos, Kuan Yan, Lucia Salinaro, Lex Bakker, john de Kruif, Hans Clevers, Robert Vries, Eduard Batlle, Leo Price, Mark Throsby. Preclinical evaluation of MCLA-158: A bispecific antibody targeting LGR5 and EGFR using patient-derived colon carcinoma organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 32. doi:10.1158/1538-7445.AM2017-32
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-32
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
