Reference Detail

Ref Type

Journal Article

PMID

(30962319)

Authors

He K, Xu J, Liang J, Jiang J, Tang M, Ye X, Zhang Z, Zhang L, Fu B, Li Y, Bai C, Zhang L, Tao W

Title

Discovery of A Novel EGFR-Targeting Antibody-Drug Conjugate, SHR-A1307, for the Treatment of Solid Tumors Resistant or Refractory to Anti-EGFR Therapies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	18	6	2019 Jun	1104-1114	Mol Cancer Ther

URL

Abstract Text

Although inhibiting EGFR-mediated signaling proved to be effective in treating certain types of cancers, a quickly evolved mechanism that either restores the EGFR signaling or activates an alternative pathway for driving the proliferation and survival of malignant cells limits the efficacy and utility of the approach via suppressing the EGFR functionality. Given the fact that overexpression of EGFR is commonly seen in many cancers, an EGFR-targeting antibody-drug conjugate (ADC) can selectively kill cancer cells independently of blocking EGFR-mediated signaling. Herein, we describe SHR-A1307, a novel anti-EGFR ADC, generated from an anti-EGFR antibody with prolonged half-life, and conjugated with a proprietary toxin payload that has increased index of EGFR targeting-dependent versus EGFR targeting-independent cytotoxicity. SHR-A1307 demonstrated strong and sustained antitumor activities in EGFR-positive tumors harboring different oncogenic mutations on EGFR, KRAS, or PIK3CA. Antitumor efficacy of SHR-A1307 correlated with EGFR expression levels in vitro and in vivo, regardless of the mutation status of EGFR signaling mediators and a resultant resistance to EGFR signaling inhibitors. Cynomolgus monkey toxicology study showed that SHR-A1307 is well tolerated with a wide therapeutic index. SHR-A1307 is a promising therapeutic option for EGFR-expressing cancers, including those resistant or refractory to the EGFR pathway inhibitors.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
SHR-A1307	SHR-A1307	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SHR-A1307			EGFR Antibody 60	SHR-A1307 is an antibody-drug conjugate that consists of an auristatin analog linked to the anti-EGFR antibody Nimotuzumab with improved half-life, which inhibits cell growth in culture and reduces tumor growth (PMID: 30962319).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA H1047R	head and neck squamous cell carcinoma	predicted - sensitive	SHR-A1307	Preclinical - Cell culture	Actionable	In a preclinical study, head and neck squamous cell carcinoma cells harboring PIK3CA H1047R treated with SHR-A1307 demonstrated inhibition of cell growth in culture (PMID: 30962319).	30962319
PIK3CA H1047R	head and neck squamous cell carcinoma	resistant	Cetuximab	Preclinical - Cell culture	Actionable	In a preclinical study, head and neck squamous cell carcinoma cells harboring PIK3CA H1047R were resistant to Erbitux (cetuximab) in culture (PMID: 30962319).	30962319