Anti-DLL3 ADC (IntoCell/Y-Biologics)(Anti-DLL3 ADC (IntoCell/Y-Biologics)) - 药物靶点：DLL3_在研适应症：实体瘤_专利_临床

概要

基本信息

药物类型

ADC

别名

anti-DLL3 ADC (IntoCell/Y-Biologics)、anti-DLL3 antibody-drug conjugate (IntoCell Inc/Y-Biologics)

靶点

DLL3

作用机制

DLL3调节剂(δ样蛋白-3调节剂)

治疗领域

肿瘤

在研适应症

实体瘤

非在研适应症-

原研机构

IntoCell, Inc.初创企业

在研机构

IntoCell, Inc.初创企业

YBiologics, Inc.

非在研机构-

最高研发阶段药物发现

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 Anti-DLL3 ADC (IntoCell/Y-Biologics) 相关的临床结果

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100 项与 Anti-DLL3 ADC (IntoCell/Y-Biologics) 相关的转化医学

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100 项与 Anti-DLL3 ADC (IntoCell/Y-Biologics) 相关的专利（医药）

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3

项与 Anti-DLL3 ADC (IntoCell/Y-Biologics) 相关的文献（医药）

2020-02-01·EBioMedicine1区 · 医学

Near infrared photoimmunotherapy targeting DLL3 for small cell lung cancer

1区 · 医学

ArticleOA

作者: Koike, Chiaki ; Kawaguchi, Koji ; Fukui, Takayuki ; Shimizu, Misae ; Hasegawa, Yoshinori ; Takahashi, Kazuomi ; Sato, Kazuhide ; Nakamura, Shota ; Baba, Yoshinobu ; Kuramoto, Noriko ; Taki, Shunichi ; Chen-Yoshikawa, Toyofumi F ; Yukawa, Hiroshi ; Endo, Rena ; Yasui, Hirotoshi ; Isobe, Yoshitaka ; Nishinaga, Yuko

BACKGROUND:

Small cell lung cancer (SCLC) has a poor prognosis, and its treatment options are limited. Delta-like protein 3 (DLL3) is expressed specifically in SCLC and is considered a promising therapeutic target for patients with this disease. Rovalpituzumab tesirine (Rova-T) was the first antibody-drug conjugate targeting DLL3. Although Rova-T development was unfortunately terminated, DLL3 remains an ideal target for SCLC. Near infrared photoimmunotherapy (NIR-PIT) is a new form of cancer treatment that employs an antibody-photosensitiser conjugate followed by NIR light exposure and damage target cells specifically. In this study, we demonstrate DLL3-targeted NIR-PIT to develop a novel molecularly targeted treatment for SCLC.

METHODS:

The anti-DLL3 monoclonal antibody rovalpituzumab was conjugated to an IR700 photosensitiser (termed 'rova-IR700'). SCLC cells overexpressing DLL3 as well as non-DLL3-expressing controls were incubated with rova-IR700 and then exposed to NIR-light. Next, mice with SCLC xenografts were injected with rova-IR700 and irradiated with NIR-light.

FINDINGS:

DLL3-overexpressing cells underwent immediate destruction upon NIR-light exposure, whereas the control cells remained intact. The xenograft in mice treated with rova-IR700 and NIR-light shrank markedly, whereas neither rova-IR700 injection nor NIR-light irradiation alone affected tumour size.

INTERPRETATION:

Our data suggest that targeting of DLL3 using NIR-PIT could be a novel and promising treatment for SCLC.

FUNDING:

Research supported by grants from the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, JSPS), Medical Research Encouragement Prize of The Japan Medical Association, The Nitto Foundation, Kanae Foundation for the Promotion of Medical Science.

2019-02-15·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase–mutant Glioma

1区 · 医学

Article

作者: Golfinos, John G. ; Sen, Namita ; Placantonakis, Dimitris G. ; Wakimoto, Hiroaki ; Zagzag, David ; Tsirigos, Aristotelis ; Chi, Andrew S. ; Riina, Howard A. ; Tateishi, Kensuke ; Shen, Guomiao ; Nicolaides, Theodore P. ; Zeck, Briana ; Cahill, Daniel P. ; Jain, Rajan ; Frenster, Joshua D. ; Isse, Kumiko ; Vasudevaraja, Varshini ; Kurz, Sylvia C. ; Chiriboga, Luis ; Sulman, Erik P. ; Spino, Marissa ; Snuderl, Matija ; Serrano, Jonathan ; Patel, Seema ; Saunders, Laura R. ; Suryadevara, Carter M.

Abstract:

Purpose::

Isocitrate dehydrogenase (IDH)-mutant glioma is a distinct glioma molecular subtype for which no effective molecularly directed therapy exists. Low-grade gliomas, which are 80%–90% IDH-mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by IHC in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody–drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in IDH-mutant glioma.

Experimental Design::

We evaluated DLL3 expression by RNA using TCGA data and by IHC in a discovery set of 63 gliomas and 20 nontumor brain tissues and a validation set of 62 known IDH wild-type and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous IDH-mutant glioma tumorspheres was determined by cell viability assay.

Results::

Compared to IDH wild-type glioblastoma, IDH-mutant gliomas have significantly higher DLL3 RNA (P < 1 × 10−15) and protein by IHC (P = 0.0014 and P < 4.3 × 10−6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH-mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 nontumor brains. Patient-derived IDH-mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner.

Conclusions::

DLL3 is selectively and homogeneously expressed in IDH-mutant gliomas and can be targeted with Rova-T in patient-derived IDH-mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.

Journal of Translational Medicine

DB-1314, a novel DLL3-targeting ADC with DNA topoisomerase I inhibitor, exhibits promising safety profile and therapeutic efficacy in preclinical small cell lung cancer models

Article

作者: Yao, Jun ; Zhu, Zhongyuan ; Lin, Shengchao ; Yang, Junjie ; Hua, Haiqing ; Qiu, Yang ; Zhang, Yu

BACKGROUND:

Delta-like ligand 3 (DLL3) is highly expressed on the cell surface of small cell lung cancer (SCLC), one of the most lethal malignancies, but minimally or not in normal tissues, making it an attractive target for SCLC. However, none of the DLL3-targeting antibody-drug conjugates (ADCs) have been approved for SCLC therapy yet. We developed DB-1314, the new anti-DLL3 ADC composed of a novel humanized anti-DLL3 monoclonal antibody (DB131401) conjugated with eight molecules of P1021 (topoisomerase I inhibitor), and described its preclinical profiles.

METHODS:

The binding epitope for DB131401 and Rovalpituzumab was tested by biolayer interferometry. The binding affinity and specificity of DB-1314 to DLL3 and other homologous proteins were respectively measured by surface plasmon resonance and enzyme-linked immunosorbent assay. Internalization, bystander effects, and antibody-dependent cell-mediated cytotoxicity (ADCC) were assessed by respective assay. DLL3 was quantified by antibodies bound per cell assay and immunohistochemistry. In vitro and in vivo growth inhibition studies were evaluated in SCLC cell lines, and cell line/patient-derived xenograft models. The safety profile was measured in cynomolgus monkeys.

RESULTS:

DB-1314 induces potent, durable, and dose-dependent antitumor effects in cells in vitro and in cell/patient-derived xenograft models in vivo. The killing activity of DB-1314 mechanically arises from P1021-induced DNA damage, whereby P1021 is delivered and released within tumor cells through DLL3-specific binding and efficient internalization. Bystander effects and ADCC also contribute to the antitumor activity of DB-1314. DB-1314 displays favorable pharmacokinetic and toxicokinetic profiles in rats and cynomolgus monkeys; besides, DB-1314 is well-tolerated at a dose of up to 60 mg/kg in monkeys.

CONCLUSIONS:

These results suggest that DB-1314 may be a candidate ADC targeting DLL3 for the treatment of DLL3-positive SCLC, supporting further evaluation in the clinical setting.

100 项与 Anti-DLL3 ADC (IntoCell/Y-Biologics) 相关的药物交易

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