Delving into the Latest Updates on Legubicin with Synapse

Overview

Basic Info

Drug Type

Small molecule-drug conjugates

Synonyms

Target

DNA x Top II

Mechanism

DNA intercalators, Top II inhibitors(Topoisomerase II inhibitors)

Therapeutic Areas

NeoplasmsOther DiseasesSkin and Musculoskeletal Diseases+ [3]

Active Indication

Soft Tissue SarcomaAdenocarcinoma of LungBreast Cancer+ [5]

Inactive Indication-

Originator Organization

Shanghai Affinity Biopharmaceutical Co., Ltd.

Active Organization

Shanghai Affinity Biopharmaceutical Co., Ltd.

Inactive Organization-

Drug Highest PhasePhase 3

First Approval Date-

RegulationSpecial Review Project (CN)

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Structure

Molecular FormulaC48H64N6O18

InChIKeyMXJIXMIBWBRASS-UGZZBAIUSA-N

CAS Registry606967-53-7

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Gene Sequence

Sequence Code 2117244

主要目的：评估注射用莱古比星治疗晚期软组织肉瘤受试者的有效性是否非劣/优效于注射用盐酸多柔比星；评估注射用莱古比星治疗晚期软组织肉瘤受试者的心脏毒性是否低于注射用盐酸多柔比星。次要目的：评价注射用莱古比星在晚期软组织肉瘤受试者中的客观缓解率（ORR）、总生存期（OS）、疾病控制率（DCR）；评价注射用莱古比星在晚期软组织肉瘤受试者中的安全性。

[Translation]

Primary objectives: To evaluate whether the effectiveness of Legubicin for Injection in treating subjects with advanced soft tissue sarcoma is non-inferior/superior to Doxorubicin Hydrochloride for Injection; To evaluate whether the cardiotoxicity of Legubicin for Injection in treating subjects with advanced soft tissue sarcoma is lower than that of Doxorubicin Hydrochloride for Injection. Secondary objectives: To evaluate the objective response rate (ORR), overall survival (OS), and disease control rate (DCR) of Legubicin for Injection in subjects with advanced soft tissue sarcoma; To evaluate the safety of Legubicin for Injection in subjects with advanced soft tissue sarcoma.

Start Date11 Feb 2022

Sponsor / Collaborator

Shanghai Affinity Biopharmaceutical Co., Ltd.

CTR20192606 / RecruitingPhase 1

评价注射用莱古比星治疗晚期恶性实体瘤患者的安全性、耐受性、药代动力学特征以及初步疗效的Ⅰ期临床试验

[Translation] A phase I clinical trial to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of Legubicin for injection in the treatment of patients with advanced malignant solid tumors

主要目的：评价注射用莱古比星单药在标准治疗失败的晚期恶性实体瘤患者中的安全性和耐受性，并探索注射用莱古比星的最大耐受剂量（MTD），确定II期临床试验推荐剂量（RP2D）。次要目的： 1）评价注射用莱古比星的药代动力学（PK）特征； 2）初步评价注射用莱古比星的抗肿瘤疗效。 3）探索注射用莱古比星的药效学指标。

[Translation]

Primary objective: To evaluate the safety and tolerability of Legubicin for Injection as a single agent in patients with advanced malignant solid tumors who have failed standard treatment, and to explore the maximum tolerated dose (MTD) of Legubicin for Injection and determine the recommended dose (RP2D) for Phase II clinical trials. Secondary objectives: 1) To evaluate the pharmacokinetic (PK) characteristics of Legubicin for Injection; 2) To preliminarily evaluate the anti-tumor efficacy of Legubicin for Injection. 3) To explore the pharmacodynamic indicators of Legubicin for Injection.

Start Date14 May 2020

Sponsor / Collaborator

Shanghai Affinity Biopharmaceutical Co., Ltd.

100 Clinical Results associated with Legubicin

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100 Translational Medicine associated with Legubicin

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100 Patents (Medical) associated with Legubicin

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3

Literatures (Medical) associated with Legubicin

01 Sep 2024·Journal of Applied Toxicology

Biodistribution and preclinical safety profile of legubicin: A novel conjugate of doxorubicin and a legumain‐cleavable peptide linker

Article

Author: Liu, Cheng ; Qiu, Yunliang ; Wei, Liping ; Wang, Le ; Wang, Yan ; JingMa ; Li, Hua ; Zhou, Lu ; Liu, Yuan ; Hou, Minbo

AbstractLegubicin is a novel conjugate of doxorubicin and a legumain‐cleavable peptide linker. It has been developed to ameliorate the side effects of doxorubicin. Biodistribution in tumor‐bearing mice, acute tolerance, and potential systemic toxic effects in Sprague–Dawley rats and beagle dogs of legubicin were assessed. Legubicin exists mainly as a protein complex in plasma after entering the circulation. Compared with conventional doxorubicin at an equal molar dose in mice, we found higher exposure to doxorubicin in tumor (approximately 1.7‐fold increase) while lower exposure in normal tissues (an ~3.26‐, 3.46‐, and 1.29‐fold reduction in heart, kidney, and plasma, respectively) in tumor‐bearing mice after intravenous injection of legubicin. The acute maximum tolerance dose (MTD) of legubicin was >16 mg/kg doxorubicin equivalent in female rats, 11 mg/kg doxorubicin equivalent in male rats (LD50 of conventional doxorubicin is 10.51 mg/kg), and >8 mg/kg doxorubicin equivalent in dogs (MTD of conventional doxorubicin is 1.5 mg/kg). Four‐week repeat‐dose toxicity studies of intravenous legubicin were conducted in rats (5, 10, and 25 mg/kg/dose once weekly) and dogs (3/1.5, 10/5, and 20/10 mg/kg/dose once weekly); the dose levels were reduced from the second dose due to intolerable legubicin‐associated toxicity at 20 mg/kg. Major organs of toxicity included the gastrointestinal tract, lymphoid and hematopoietic organs, kidney, skin, liver, reproductive organs, and peripheral nerves, which are all associated with doxorubicin. However, cardiotoxicity was only noted at MTD dose levels. Altogether, our results confirm an improved safety profile of legubicin over conventional doxorubicin and support its clinical benefit for treating cancer.

01 Jun 2003·Cancer research

Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy.

Article

Author: Sun, Chengzao ; Liu, Cheng ; Huang, Haining ; Edgington, Thomas ; Janda, Kim

Expression of legumain, a novel asparaginyl endopeptidase, in tumors was identified from gene expression profiling and tumor tissue array analysis. Legumain was demonstrated in membrane-associated vesicles concentrated at the invadopodia of tumor cells and on cell surfaces where it colocalized with integrins. Legumain was demonstrated to activate progelatinase A. Cells overexpressing legumain possessed increased migratory and invasive activity in vitro and adopted an invasive and metastatic phenotype in vivo, inferring significance of legumain in tumor invasion and metastasis. A prodrug strategy incorporating a legumain-cleavable peptide substrate onto doxorubicin was developed. The prototype compound, designated legubicin, exhibited reduced toxicity and was effectively tumoricidal in vivo in a murine colon carcinoma model.

Molecules

UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies

Article

Author: Chang, Yan ; Yang, Chen ; Li, Yuling ; Liu, Cheng ; Ma, Liyuan ; Liu, Yuan ; Shen, Xiaoyan ; Yu, Qiaoling ; Zhuang, Meng

Legubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing mice following intravenous administration, and to compare this prodrug with the positive control drug doxorubicin. The study employed a UHLC-MS/MS method to determine the levels of albumin-bound of legubicin and two metabolites (free Leu-DOX and DOX) in plasma, tumor, and tissue samples. This method was validated for good selectivity, high sensitivity, excellent extraction recovery, and short run time. The results showed that legubicin was present in the circulation in vivo mainly in a protein-bound form with larger AUC values and lower clearance and distribution, and essentially released small amounts of doxorubicin. Compared to administration of equimolar doses of doxorubicin, legubicin showed increased exposure of the active drug in the tumor and decreased the level of the active drug in the heart and kidney. This study provides valuable information on the pharmacokinetics and tissue distribution of legubicin, implicating its potential as a novel and effective drug candidate for anti-cancer therapies.

100 Deals associated with Legubicin

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Soft Tissue Sarcoma	Phase 3	-	Shanghai Affinity Biopharmaceutical Co., Ltd.	-
Adenocarcinoma of Lung	Phase 2	-	Shanghai Affinity Biopharmaceutical Co., Ltd.	-
Breast Cancer	Phase 2	CN	Shanghai Affinity Biopharmaceutical Co., Ltd.	-
Advanced Malignant Solid Neoplasm	Phase 1	CN	Shanghai Affinity Biopharmaceutical Co., Ltd.	14 May 2020
Advanced Lung Non-Small Cell Carcinoma	IND Approval	CN	Shanghai Affinity Biopharmaceutical Co., Ltd.	26 Aug 2024
Glioma	IND Approval	CN	Shanghai Affinity Biopharmaceutical Co., Ltd.	28 Jun 2023
Stomach Cancer	IND Approval	CN	Shanghai Affinity Biopharmaceutical Co., Ltd.	28 Jun 2023
Triple Negative Breast Cancer	IND Approval	CN	Shanghai Affinity Biopharmaceutical Co., Ltd.	28 Jun 2023