Reference Detail

Ref Type

Abstract

PMID

Authors

S. Lin Y. Zhang B. Li R. Shi Y. Qiu H. Hua

Title

DB-1303, a HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising safety profile and anti-tumor efficacy with differentiation from DS-8201a

Journal	Vol	Issue	Date	Pages	Journal Short Title
European Journal of Cancer	174	Supplement 1	October 01, 2022

URL

https://www.ejcancer.com/article/S0959-8049(22)01040-1/fulltext

Abstract Text

Background: DB-1303 is a novel antibody-drug conjugate comprised of trastuzumab biosimilar, enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor P1003. It is designed to have high plasma stability, low free payload in circulation and wide therapeutic index. Herein, we describe the preclinical profile of DB-1303, including efficacy, pharmacokinetics, and safety. Material and Methods: In vitro cell growth inhibition and in vivo antitumor activities of DB-1303 were evaluated in several Her2-low tumor cell lines and xenograft models. Tumor-bearing mice were used to assess pharmacokinetic and pharmacodynamic characteristic of DB-1303. The mechanism of action for the efficacy was also evaluated. Plasma stability of DB-1303 was determined with rat, monkey, and human plasma. Pharmacokinetic and safety profiles of DB-1303 were evaluated in cynomolgus monkeys. Results: In vitro, DB-1303 selectively binds to and is endocytosed into the lysosome of HER2-positive cells. DB-1303 causes G2/M cell cycle arrest, induces DNA damage, and inhibits cell proliferation in HER2-expressing cells. Importantly, DB-1303 showed inhibitory activity to Her2 low-expressing CAPAN-1 (pancreatic cancer) and Ishikawa (endometrial cancer) cell lines. Under a coculture condition of HER2-positive KPL-4 cells and HER2-negative MDA-MB-468 cells in vitro, DB-1314 inhibited the proliferation of both cells, demonstrating its bystander effect. In vivo, DB-1303 induced dose-dependent tumor growth inhibition and tumor regression in T-DM1-resistant JIMT-1 xenograft model, HER2 low-expressing Ishikawa xenograft and two HER2-low breast cancer PDX models. A single dosing of DB-1303 in NCI-N87 tumor-bearing mice induced significant DNA damage in tumors, and the Cmax of payload in tumor tissues was about 45-fold higher than that in peripheral blood. Pharmacokinetics and safety profiles of DB-1303 were favorable and the highest non-severely toxic dose was 80 mg/kg in cynomolgus monkey study with Q3W dosing of 3 repeated doses. It’s worth noting that, unlike DS-8201a, no interstitial pneumonia was observed in monkeys during the dosing period and recovery period. The payload P1003 poses very low risk of drug-drug interaction. Following administration of DB-1303, systemic P1003 exposure was low and P1003 was cleared rapidly. Conclusions: DB-1303 exhibited potent antitumor activity in both HER2 positive and HER2 low tumor models with a wide therapeutic window. The stable linker in circulation and fast clearance of P1003 may contribute to the superior safety profile of DB-1303. These studies suggest the potential of DB-1303 to address unmet medical needs in HER2 expressing cancers, especially in HER2 low cancers. At the time of presentation, a first-in-human phase 1/2 study in patients with advanced solid tumors is in progress (NCT05150691).

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
DB-1303	DB-1303	0	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
DB-1303		DB1303\|DB 1303	HER2 (ERBB2) Antibody 74 HER2 (ERBB2) Antibody-Drug Conjugate 29	DB-1303 is an antibody-drug conjugate (ADC) composed of a biosimilar to the ERBB2 (HER2)-targeted antibody Herceptin (trastuzumab) conjugated to the topoisomerase I inhibitor P1003, which potentially leads to growth inhibition of ERBB2 (HER2)-expressing tumor cells and tumor regression (European Journal of Cancer 174 (2022): S91).

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