From AVATAR Mice to Patients: RC48-ADC Exerted Promising Efficacy in Advanced Gastric Cancer With HER2 Expression.

Zuhua Chen,Lin Shen,Cheng Zhang,Jing Gao,Jifang Gong,Yingying Xu,Jiajia Yuan,Yanyan Li,Zhongwu Li

doi:10.3389/fphar.2021.757994

Abstract

RC48-ADC is a novel humanized antibody specific for human epidermal growth factor receptor 2 (HER2)in conjugation with a microtubule inhibitor via a cleavable linker. This study was to evaluate the antitumor activity and mechanism of RC48-ADC in gastric cancer (GC) and explore the population that may benefit from RC48-ADC treatment. Four human GC cell lines and nine patient-derived xenograft (PDX) models were exploited to evaluate the antitumor effect of RC48-ADC or trastuzumab treatment in vitro and in vivo. The expression and phosphorylation of HER2 were assessed by immunohistochemistry (IHC) staining. Critical molecules of downstream PI3K/AKT and cell cycle and apoptosis signaling pathways were detected and quantified by immunoblotting. Combined with preliminary results of preclinical research, three patients with IHC3+, IHC2+/FISH+, and IHC2+/FISH- of HER2 were enrolled to verify the efficacy of RC48-ADC treatment in advanced GC. In vitro, RC48-ADC had superior antiproliferative effects in a dose-dependent manner on GC cells, especially on HER2-positive cells. In vivo, RC48-ADC exceeded trastuzumab in GC PDX models with HER2 expression, even in models with moderate to low expression of HER2. Further exploration of mechanism showed that RC48-ADC exerted the antitumor effect by inhibiting phosphorylation of HER2, inducing G2/M phase arrest and cell apoptosis in HER2-expressed PDX models. In clinical practice, RC48-ADC had satisfactory efficacy in HER2-positive and HER2 moderately expressed GC patients and demonstrated promising efficacy in HER2-positive patients who have progressed after anti-HER2 therapy. In conclusion, RC48-ADC exerted promising antitumor activity in HER2-positive as well as score of 2+ in IHC and ISH-negative AGC patients after progression of systematic treatment.

Highlights

Antibody–drug conjugates (ADCs), a conjugation of a monoclonal antibody, a payload cytotoxic agent, and chemical linkers, have emerged as a promising anticancer strategy for the past decades (Abdollahpour-Alitappeh et al, 2019)
Cell viability tests wereconducted to evaluate the antitumor activity of RC48-ADC on 4 gastric cancer (GC) cell lines, followed by protein expression analysis to clarify the profiling of those cells
In patient-derived xenograft (PDX) models with high expression (IHC3+) and amplification (FISH+) of human epidermal growth factor receptor 2 (HER2) (Figure 2B, Table 1), the antitumor activity of RC48-ADC was significantly superior to trastuzumab in PDX1 (TGI: 134% vs. 68%, p < 0.001) and equivalent to trastuzumab in three other models (TGI: 94%–126% vs. 82%–125%)

Summary

Introduction

Antibody–drug conjugates (ADCs), a conjugation of a monoclonal antibody, a payload cytotoxic agent, and chemical linkers, have emerged as a promising anticancer strategy for the past decades (Abdollahpour-Alitappeh et al, 2019). ADCs have tumor specificity and antitumor potency not achievable with traditional drugs, through the cellular process of antibody–antigen binding on cancer cell surface, endocytosis into the cell, and releasing of cytotoxin (Hafeez et al, 2020). ADCs including Adcetris®, Akalux®, Besponsa®, Blenrep®, Enhertu®, Lumoxiti®, Mylotarg®, Polivy®, Trodelvy®, and Kadcyla® have been approved for cancer therapy by the US. Trastuzumab is a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) that exerts antitumor activity by mediating antibody-dependent cellular cytotoxicity (ADCC), inhibiting of HER2-mediated signal transduction, and shedding of HER2-extracellular domain (ECD) (Hudis, 2007). Trastuzumab has been approved in the treatment of HER2-positive patients with breast cancer (BC) (Slamon et al, 2001; Piccart-Gebhart et al, 2005) and advanced gastric cancer (AGC) (Bang et al, 2010).

Methods

Results

Conclusion