scholarly journals Effectiveness of Antibody-Drug Conjugate (ADC): Results of In Vitro and In Vivo Studies

2018 ◽  
Vol 24 ◽  
pp. 1408-1416 ◽  
Author(s):  
Xiuhua Kang ◽  
Li Zhou ◽  
Ya-mei Jian ◽  
Shao-an Lan ◽  
Fei Xu
Keyword(s):  
In Vivo Studies ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

scholarly journals SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/neu expression.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14009-e14009
Author(s):  
Gulden Menderes ◽  
Elena Bonazzoli ◽  
Stefania Bellone ◽  
Jonathan Black ◽  
Gary Altwerger ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Gynecological Cancer ◽  
In Vivo Studies ◽  
Her2 Overexpression ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Bystander Killing ◽  
Antibody Drug

e14009 Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. HER2 overexpression/amplification in EOC show considerable variation ranging from 8% to 66%. SYD985 (Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands) is a novel HER2-targeting antibody-drug conjugate (ADC) composed of the monoclonal antibody (mAb) trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin). The objective of this study was to compare the anti-tumor activity of SYD985 to trastuzumab emtansine (T-DM1) in EOC. Methods: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. Results: SYD985 and T-DM1 induced similar ADCC in the presence of effector cells [i.e., peripheral blood lymphocytes (PBL)] against EOC cell lines with high, moderate and low HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1. Specifically, in HER2/neu 1+ cell lines the mean IC50’s were 0.072 µg/mL and 3.035 µg/mL for SYD985 vs T-DM1 (p < 0.0001), in HER2/neu 2+ cell lines 0.054 µg/mL and 1.168 µg/mL, (p < 0.0001) and in HER2/neu 3+ cell lines 0.024 µg/mL and 0.088 µg/mL, respectively, (p < 0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ EOC cells admixed with HER2/neu 3+ cells. In vivo studies confirmed that SYD985 is more active than T-DM1 in EOC and effective against HER2/neu 3+ xenografts. Additional (HER2/neu 2+ & 1+) EOC xenograft studies are ongoing. Conclusions: SYD985 is a novel ADC with remarkable in vitro activity against EOC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it may be active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in EOC patients harboring chemo-resistant disease are needed.

Abstract 2651: A novel CD19 targeting antibody-drug conjugate, huB4-DGN462, shows promising in vitro and in vivo activity in CD19-positive lymphoma models

2017 ◽  
Author(s):  
Eugenio Gaudio ◽  
Chiara Tarantelli ◽  
Alberto J. Arribas ◽  
Roberta Pittau Bordone ◽  
Andrea Rinaldi ◽  
...  
Keyword(s):  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

In vitro and in vivo catabolism of TAK-164, a gcc-targeted antibody-drug conjugate

2019 ◽  
Vol 34 (1) ◽  
pp. S20-S21
Author(s):  
Jayaprakasam Bolleddula ◽  
Mohammad Shadid ◽  
Abhi Shah ◽  
Afrand Kamali ◽  
Mike Smith ◽  
...  
Keyword(s):  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma

2021 ◽  
Vol 162 ◽  
pp. S186-S187
Author(s):  
Joan Tymon-Rosario ◽  
Elena Bonazzoli ◽  
Adele Guglielmi ◽  
Stefania Bellone ◽  
Nupur Nagarkatti ◽  
...  
Keyword(s):  
Serous Carcinoma ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Uterine Serous Carcinoma ◽  
Antibody Drug

SYD985, a novel HER2-targeting antibody-drug conjugate in preclinical models for USC, both in vitro and in vivo.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. e16527-e16527 ◽  
Author(s):  
Jonathan Black ◽  
Salvatore Lopez ◽  
Emiliano Cocco ◽  
Stefania Bellone ◽  
Elena Bonazzoli ◽  
...  
Keyword(s):  
Preclinical Models ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

scholarly journals Antibody–Drug Conjugate to Treat Meningiomas

2021 ◽  
Vol 14 (5) ◽  
pp. 427
Author(s):  
Kai Chen ◽  
Yingnan Si ◽  
Jianfa Ou ◽  
Jia-Shiung Guan ◽  
Seulhee Kim ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Imaging System ◽  
Somatostatin Receptor ◽  
Antibody Drug Conjugate ◽  
Primary Tumors ◽  
Drug Conjugate ◽  
Binding Rate ◽  
Antibody Drug

Meningiomas are primary tumors of the central nervous system with high recurrence. It has been reported that somatostatin receptor 2 (SSTR2) is highly expressed in most meningiomas, but there is no effective targeted therapy approved to control meningiomas. This study aimed to develop and evaluate an anti-SSTR2 antibody–drug conjugate (ADC) to target and treat meningiomas. The meningioma targeting, circulation stability, toxicity, and anti-tumor efficacy of SSTR2 ADC were evaluated using cell lines and/or an intracranial xenograft mouse model. The flow cytometry analysis showed that the anti-SSTR2 mAb had a high binding rate of >98% to meningioma CH157-MN cells but a low binding rate of <5% to the normal arachnoidal AC07 cells. The In Vivo Imaging System (IVIS) imaging demonstrated that the Cy5.5-labeled ADC targeted and accumulated in meningioma xenograft but not in normal organs. The pharmacokinetics study and histological analysis confirmed the stability and minimal toxicity. In vitro anti-cancer cytotoxicity indicated a high potency of ADC with an IC50 value of <10 nM. In vivo anti-tumor efficacy showed that the anti-SSTR2 ADC with doses of 8 and 16 mg/kg body weight effectively inhibited tumor growth. This study demonstrated that the anti-SSTR2 ADC can target meningioma and reduce the tumor growth.

scholarly journals 854 SGN-B7H4V, a novel, investigational vedotin antibody-drug conjugate directed to the T cell checkpoint ligand B7-H4, shows promising activity in preclinical models

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A895-A895
Author(s):  
Elizabeth Gray ◽  
Angela Epp ◽  
Michelle Ulrich ◽  
Disha Sahetya ◽  
Kelly Hensley ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Immune Checkpoint ◽  
Brentuximab Vedotin ◽  
Preclinical Models ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Tumor Types ◽  
Antibody Drug

BackgroundSGN-B7H4V is a novel, investigational vedotin antibody drug conjugate (ADC) directed to B7-H4, a member of the B7 family of immune checkpoint ligands. B7-H4 expression is elevated on a variety of solid tumors including breast, ovarian, and endometrial tumors.1 SGN-B7H4V is composed of a fully human IgG1 anti-B7-H4 monoclonal antibody (mAb) conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable peptide linker. SGN-B7H4V is designed to bind and internalize the immune checkpoint ligand B7-H4/ADC complex from the surface of malignant cells and release the cytotoxic payload MMAE. This ”vedotin” drug linker system has been clinically validated by multiple ADC programs, including brentuximab vedotin, enfortumab vedotin, and polatuzumab vedotin.2–4 Here, we characterize the target antigen B7-H4 and evaluate SGN-B7H4V activity in preclinical models.MethodsB7-H4 expression was characterized by RNA expression and immunohistochemistry across multiple solid tumor types. The ability of SGN-B7H4V to kill B7-H4-expressing tumor cells in vitro and in vivo in a variety of xenograft tumor models was also evaluated. Finally, the tolerability of SGN-B7H4V was assessed in rodent and non-human primate toxicology studies.ResultsImmunohistochemistry confirmed expression of B7-H4 across multiple solid tumor types, including ovarian and breast tumors. In vitro, upon binding to SGN-B7H4V, the immune checkpoint ligand B7-H4 was rapidly internalized and delivered the cytotoxic payload MMAE. Moreover, SGN-B7H4V killed B7-H4-expressing tumor cells in vitro by MMAE-mediated cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). In vivo, SGN-B7H4V demonstrated strong anti-tumor activity in multiple xenograft models, including ovarian and breast cancer models. Activity was observed in models with both uniformly high and heterogeneous expression of B7-H4, consistent with robust bystander activity of vedotin ADCs. Finally, SGN-B7H4V was tolerated in both rat and non-human primate (NHP) toxicology studies at doses consistent with approved vedotin ADCs.ConclusionsB7-H4 is a promising ADC target expressed by several solid tumor types. SGN-B7H4V demonstrates robust anti-tumor activity in preclinical models through multiple potential mechanisms and is tolerated in rat and NHP toxicity studies. Altogether, these data support further evaluation of SGN-B7H4V in a planned, first-in-human phase 1 clinical study.AcknowledgementsWe would like to thank Kellie Spahr for conjugation support and Martha Anderson for in vivo biology support.ReferencesLeong SR, Liang WC, Wu Y, Crocker L, Cheng E, Sampath D, et al. An anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer. Mol Pharm 2015;12(6):1717–29. Epub 2015/04/09. doi: 10.1021/mp5007745. PubMed PMID: 25853436.Rosenberg JE, O’Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 2019;37(29):2592–600. Epub 2019/07/30. doi: 10.1200/JCO.19.01140. PubMed PMID: 31356140; PubMed Central PMCID: PMC.Senter PD, Sievers EL. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol 2012;30(7):631–7. Epub 2012/07/12. doi: 10.1038/nbt.2289. PubMed PMID: 22781692.Tilly H, Morschhauser F, Bartlett NL, Mehta A, Salles G, Haioun C, et al. Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Lancet Oncol 2019;20(7):998–1010. Epub 2019/05/19. doi: 10.1016/S1470-2045(19)30091–9. PubMed PMID: 31101489.Ethics ApprovalAll animal studies were conducted in accordance with protocols reviewed and approved by the Institutional Animal Care and Use Committee at Seagen or the external testing facility that conducted the studies.

scholarly journals ABBV-176, a PRLR antibody drug conjugate with a potent DNA-damaging PBD cytotoxin and enhanced activity with PARP inhibition

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mark G. Anderson ◽  
Qian Zhang ◽  
Luis E. Rodriguez ◽  
Claudie M. Hecquet ◽  
Cherrie K. Donawho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Parp Inhibition ◽  
Breast Cancers ◽  
Dna Breaks ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Patient Derived Xenograft ◽  
Antibody Drug

Abstract Background Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations. Methods We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models. Results In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage. Conclusions Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.

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