89Zr-durvalumab(89Zr-durvalumab) - 药物靶点：PDL1_在研适应症：头颈部肿瘤_专利_临床

概要

基本信息

药物类型

抗体偶联核素、诊断用放射药物

别名-

靶点

PDL1

作用方式

抑制剂

作用机制

PDL1抑制剂(程序性死亡配体1抑制剂)

治疗领域

肿瘤

在研适应症

头颈部肿瘤

非在研适应症

复发性头颈部鳞状细胞癌

原研机构

Radboud University Nijmegen

在研机构

Radboud University Nijmegen

非在研机构

AstraZeneca PLC

权益机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

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Sequence Code 10069506H

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关联

12

项与 89Zr-durvalumab 相关的临床试验

ISRCTN11210442

/ RecruitingN/A

Exploring the microbiome in patients with advanced biliary tract cancer in a first-line study of durvalumab (MEDI4736) in combination with cisplatin/gemcitabine

开始日期2023-11-09

申办/合作机构-

JPRN-jRCT2031210083

/ Completed临床1期IIT

A phase Ib study of Durvalumab (MEDI4736) in combination with carbon-ion radiotherapy and weekly cisplatin for patients with locally advanced cervical cancer

开始日期2021-12-10

申办/合作机构-

EUCTR2020-001588-10-IT

/ Not yet recruiting临床2期IIT

A randomized, phase IIb study of adjuvant durvalumab (MEDI4736) plus regorafenib vs untreated control in stage IV colorectal cancer patients with no evidence of disease (NED): VIVA trial - VIVA trial

开始日期2021-09-27

申办/合作机构-

100 项与 89Zr-durvalumab 相关的临床结果

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100 项与 89Zr-durvalumab 相关的转化医学

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100 项与 89Zr-durvalumab 相关的专利（医药）

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4

项与 89Zr-durvalumab 相关的文献（医药）

2025-10-28·Blood Advances

T-cell dysregulation informs radiotherapy-immunotherapy response in B-cell lymphoma: results from a phase 1 trial

Article

作者: Shortt, Jake ; Smith, Charmaine ; MacManus, Michael ; Scott, Andrew M. ; Palmer, Jodie B. ; Chong, Geoffrey ; Chowdhury, Rakin ; Gandhi, Maher K. ; Churilov, Leonid ; Martynchyk, Arina ; Keane, Colm ; Hawkes, Eliza A. ; Law, Soi C. ; Burgess, Melinda ; Khor, Richard ; Manos, Kate ; Lee, Sze Ting ; Scott, Fiona E. ; Swain, Fiona ; Barraclough, Allison

Abstract:

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are highly radiosensitive with immune-driven abscopal responses reported. Programmed cell death 1/programmed cell death ligand 1 (PD-L1) inhibitors are relatively ineffective in DLBCL/FL; however, evidence suggests synergy with radiotherapy (RT), but no clear biomarkers. This phase 1 study examined the safety of escalating RT dose and treated volumes with durvalumab (PD-L1 inhibitor) in 34 adults with relapsed/refractory DLBCL and relapsed/refractory FL, and the role of immune-cell subsets on outcomes. Patients received external-beam RT (2.5-30 Gray [Gy], 5 or 10 fractions up to 3 target sites) plus durvalumab from RT day 2, until progression. Novel positron emission tomography (PET) biodistribution studies of 89Zr-durvalumab and CD8 T-cell minibody-89Zr-Df-crefmirlimab were incorporated. The RT recommended phase 2 dose was 10 Gy/5 fractions and 30 Gy/10 fractions to 3 sites for FL and DLBCL, respectively. The most common grade 3 to 4 toxicities included anemia (9%), neutropenia (11%), and liver dysfunction (5%). Overall response was 60% in FL (3/5; complete response, 40% [2/5]), and 14% in DLBCL (4/27; complete response, 7% [2/27]). Distinct peripheral blood and tumor T-cell features, including CD8 PET–determined intratumoral CD8 T-cells, correlated with response (P < .05). RT-durvalumab with 30 Gy/10 fractions of RT to 3 disease sites is safe, and offers promising responses in FL. Intratumoral and peripheral blood CD8 T-cell dysregulation correlate with treatment response. This trial was registered at www.clinicaltrials.gov as #NCT03610061.

2023-05-01·Nuclear medicine and biology

Automated radiosynthesis of [89Zr]Zr-DFOSq-Durvalumab for imaging of PD-L1 expressing tumours in vivo

Article

作者: Van Zuylekom, Jessica ; Rudd, Stacey E ; Donnelly, Paul S ; MacManus, Michael ; Hegi-Johnson, Fiona ; Burvenich, Ingrid J G ; Wichmann, Christian W ; Scott, Andrew M ; Morandeau, Laurence ; Blyth, Benjamin ; Mohamed, Shifaza ; Roselt, Peter ; Nowak, Anna K ; Rigopoulos, Angela ; Guo, Nancy ; Poniger, Stan

OBJECTIVES:

⁸⁹Zr-labelled proteins are gaining importance in clinical research in a variety of diseases. To date, no clinical study has been reported that utilizes an automated approach for radiosynthesis of ⁸⁹Zr-labelled radiopharmaceuticals. We aim to develop an automated method for the clinical production of ⁸⁹Zr-labelled proteins and apply this method to Durvalumab, a monoclonal antibody targeting PD-L1 immune-checkpoint protein. PD-L1 expression is poorly understood and can be up-regulated over the course of chemo- and radiotherapy treatment. The ImmunoPET multicentre study aims to examine the dynamics of PD-L1 expression via ⁸⁹Zr-Durvalumab PET imaging before, during, and after chemoradiotherapy. The developed automated technique will enable reproducible clinical production of [⁸⁹Zr]Zr-DFOSq-Durvalumab for this study at three different sites.

METHODS:

Conjugation of Durvalumab to H₃DFOSqOEt was optimized for optimal chelator-to-antibody ratio. Automated radiolabelling of H₃DFOSq-Durvalumab with zirconium-89 was optimized on the disposable cassette based iPHASE technologies MultiSyn radiosynthesizer using a modified cassette. Activity losses were tracked using a dose calibrator and minimized by optimizing fluid transfers, reaction buffer, antibody formulation additives and pH. The biological profile of the radiolabelled antibody was confirmed in vivo in PD-L1+ (HCC827) and PD-L1- (A549) murine xenografts. Clinical process validation and quality control were performed at three separate study sites to satisfy clinical release criteria.

RESULTS:

H₃DFOSq-Durvalumab with an average CAR of 3.02 was obtained. Radiolabelling kinetics in succinate (20 mM, pH 6) were significantly faster when compared to HEPES (0.5 M, pH 7.2) with >90 % conversion observed after 15 min. Residual radioactivity in the ⁸⁹Zr isotope vial was reduced from 24 % to 0.44 % ± 0.18 % (n = 7) and losses in the reactor vial were reduced from 36 % ± 6 % (n = 4) to 0.82 % ± 0.75 % (n = 4) by including a surfactant in the reaction and formulation buffers. Overall process yield was 75 % ± 6 % (n = 5) and process time was 40 min. Typically, 165 MBq of [⁸⁹Zr]Zr-DFOSq-Durvalumab with an apparent specific activity of 315 MBq/mg ± 34 MBq/mg (EOS) was obtained in a volume of 3.0 mL. At end-of-synthesis (EOS), radiochemical purity and protein integrity were always >99 % and >96 %, respectively, and dropped to 98 % and 65 % after incubation in human serum for 7 days at 37 °C. Immunoreactive fraction in HEK293/PD-L1 cells was 83.3 ± 9.0 (EOS). Preclinical in vivo data at 144 h p.i. showed excellent SUV_max in PD-L1+ tumour (8.32 ± 0.59) with a tumour-background ratio of 17.17 ± 3.96. [⁸⁹Zr]Zr-DFOSq-Durvalumab passed all clinical release criteria at each study site and was deemed suitable for administration in a multicentre imaging trial.

CONCLUSION:

Fully automated production of [⁸⁹Zr]Zr-DFOSq-Durvalumab for clinical use was achieved with minimal exposure to the operator. The cassette-based approach allows for consecutive productions on the same day and offers an alternative to currently used manual protocols. The method should be broadly applicable to other proteins and has the potential for clinical impact considering the growing number of clinical trials investigating ⁸⁹Zr-labelled antibodies.

EJNMMI physics

How to obtain the image-derived blood concentration from 89Zr-immuno-PET scans

Article

作者: Huisman, Marc C ; Ahbari, Amina ; van Dongen, Guus A M S ; Greuter, Henri N J M ; Vugts, Daniëlle J ; Wijngaarden, Jessica E ; Menke-van der Houven van Oordt, C Willemien ; Zwezerijnen, Gerben J C ; Bahce, Idris ; Pouw, Johanna E E ; Boellaard, Ronald

Abstract:

Background:

PET scans using zirconium-89 labelled monoclonal antibodies (89Zr-mAbs), known as 89Zr-immuno-PET, are made to measure uptake in tumour and organ tissue. Uptake is related to the supply of 89Zr-mAbs in the blood. Measuring activity concentrations in blood, however, requires invasive blood sampling. This study aims to identify the best delineation strategy to obtain the image-derived blood concentration (IDBC) from 89Zr-immuno-PET scans.

Methods:

PET imaging and blood sampling of two 89Zr-mAbs were included, 89Zr-cetuximab and 89Zr-durvalumab. For seven patients receiving 89Zr-cetuximab, PET scans on 1–2 h, 2 and 6 days post-injection (p.i.) were analysed. Five patients received three injections of 89Zr-durvalumab. The scanning protocol for the first two injections consisted of PET scanning on 2, 5 and 7 days p.i. and for the third injection only on 7 days p.i. Blood samples were drawn with every PET scan and the sample-derived blood concentration (SDBC) was used as gold standard for the IDBC. According to an in-house developed standard operating procedure, the aortic arch, ascending aorta, descending aorta and left ventricle were delineated. Bland–Altman analyses were performed to assess the bias (mean difference) and variability (1.96 times the standard deviation of the differences) between IDBC and SDBC.

Results:

Overall, the activity concentration obtained from the IDBC was lower than from the SDBC. When comparing IDBC with SDBC, variability was smallest for the ascending aorta (20.3% and 17.0% for 89Zr-cetuximab and 89Zr-durvalumab, respectively). Variability for the other regions ranged between 17.9 and 30.8%. Bias for the ascending aorta was − 10.9% and − 11.4% for 89Zr-cetuximab and 89Zr-durvalumab, respectively.

Conclusions:

Image-derived blood concentrations should be obtained from delineating the ascending aorta in 89Zr-immuno-PET scans, as this results in the lowest variability with respect to sample-derived blood concentrations.

100 项与 89Zr-durvalumab 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
复发性头颈部鳞状细胞癌	临床2期	荷兰	AstraZeneca PLC	2019-04-15
头颈部肿瘤	临床2期	-	Radboud University Nijmegen	-

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03829007 (PINCH, Pubmed \| J Nucl Med) 人工标引	临床1/2期	头颈部肿瘤	33	89Zr-DFO-durvalumabdurvalumab+durvalumab	願範衊積積製願願衊鬱(醖膚選壓簾簾蓋糧膚繭) = 願鏇鹽繭憲衊繭築獵廠範製壓繭鏇鹹積繭淵齋 (築鬱鑰鬱願獵夢窪夢顧 ) 更多	积极	2022-05-05