scholarly journals Functional native disulfide bridging enables delivery of a potent, stable and targeted antibody–drug conjugate (ADC)

2015 ◽  
Vol 51 (53) ◽  
pp. 10624-10627 ◽  
Author(s):  
João P. M. Nunes ◽  
Maurício Morais ◽  
Vessela Vassileva ◽  
Eifion Robinson ◽  
Vineeth S. Rajkumar ◽  
...  
Keyword(s):  
Blood Serum ◽  
Next Generation ◽  
High Potency ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Disulfide Bridging ◽  
Antibody Drug ◽  
Excellent Stability

A next generation maleimide–ADC is shown to have excellent stability in blood serum, as well as high potency and selectivity in vitro.

scholarly journals Nonclinical Development of Next-generation Site-specific HER2-targeting Antibody–drug Conjugate (ARX788) for Breast Cancer Treatment

2020 ◽  
Vol 19 (9) ◽  
pp. 1822-1832
Author(s):  
Prathap Nagaraja Shastri ◽  
Jingjing Zhu ◽  
Lillian Skidmore ◽  
Xuejun Liang ◽  
Yanping Ji ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Breast Cancer Treatment ◽  
Next Generation ◽  
Antibody Drug Conjugate ◽  
Site Specific ◽  
Drug Conjugate ◽  
Antibody Drug

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

Increment in Drug Loading on an Antibody–Drug Conjugate Increases Its Binding to the Human Neonatal Fc Receptor in Vitro

2016 ◽  
Vol 13 (4) ◽  
pp. 1405-1412 ◽  
Author(s):  
Guillaume Brachet ◽  
Renaud Respaud ◽  
Christophe Arnoult ◽  
Corinne Henriquet ◽  
Christine Dhommée ◽  
...  
Keyword(s):  
Drug Loading ◽  
Fc Receptor ◽  
Neonatal Fc Receptor ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

scholarly journals Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiaolei Lian ◽  
Dina Kats ◽  
Samuel Rasmussen ◽  
Leah R. Martin ◽  
Anju Karki ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
The United States ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Normal Brain ◽  
Cell Models ◽  
Pontine Glioma ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

AbstractDiffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13Rα2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13Rα2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13Rα2 signaling in progression and invasion of DIPG and viability of IL13Rα2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13Rα2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13Rα2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13Rα2 antibody–drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13Rα2 expression, supporting the potential use of targeting IL13Rα2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13Rα2 ADC for DIPG.

scholarly journals EV20/NMS-P945, a Novel Thienoindole Based Antibody-Drug Conjugate Targeting HER-3 for Solid Tumors

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 483
Author(s):  
Emily Capone ◽  
Rossano Lattanzio ◽  
Fabio Gasparri ◽  
Paolo Orsini ◽  
Cosmo Rossi ◽  
...  
Keyword(s):  
Critical Role ◽  
Ovarian Cancer Cells ◽  
Antibody Drug Conjugate ◽  
Dna Minor Groove ◽  
Drug Conjugate ◽  
Downstream Signaling ◽  
Toxicological Studies ◽  
Signaling Axis ◽  
Antibody Drug

HER-3 is becoming an attractive target for antibody–drug conjugate (ADC)-based therapy. Indeed, this receptor and its ligands are found to be overexpressed in several malignancies, and re-activation of its downstream signaling axis is known to play a critical role in modulating the sensitivity of targeted therapeutics in different tumors. In this study, we generated a novel ADC named EV20/NMS-P945 by coupling the anti-HER-3 antibody EV20 with a duocarmycin-like derivative, the thienoindole (TEI) NMS-P528, a DNA minor groove alkylating agent through a peptidic cleavable linker. This ADC showed target-dependent cytotoxic activity in vitro on several tumor cell lines and therapeutic activity in mouse xenograft tumor models, including those originating from pancreatic, prostatic, head and neck, gastric and ovarian cancer cells and melanoma. Pharmacokinetics and toxicological studies in monkeys demonstrated that this ADC possesses a favorable terminal half-life and stability and it is well tolerated. These data support further EV20/NMS-P945 clinical development as a therapeutic agent against HER-3-expressing malignancies.

scholarly journals Synergistic Anti-Leukemic Activity of PARP Inhibition Combined with IMGN632, an Anti-CD123 Antibody-Drug Conjugate in Acute Myeloid Leukemia Models

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2647-2647 ◽  
Author(s):  
Claire Fritz ◽  
Scott M. Portwood ◽  
Julie Adams ◽  
Tara Cronin ◽  
Linda Lutgen-Dunckley ◽  
...  
Keyword(s):  
Dna Damage ◽  
Board Of Directors ◽  
Cell Lines ◽  
Hematological Malignancies ◽  
Parp Inhibitors ◽  
Antibody Drug Conjugate ◽  
Advisory Committees ◽  
Drug Conjugate ◽  
Antibody Drug

Abstract Background CD123 (IL-3 receptor alpha-chain) is a therapeutic target for hematological malignancies based on high expression levels in acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), and other cancers. The anti-CD123 antibody-drug conjugate (ADC), IMGN632, comprises a humanized monoclonal antibody covalently linked to a DNA - alkylating cytotoxic payload which is currently in phase 1 evaluation for relapsed/refractory CD123-positive hematological malignancies (NCT03386513). Novel approaches to enhance the efficacy of ADCs are of significant therapeutic interest. Our laboratory has previously demonstrated that the Poly ADP Ribose (PARP) inhibitor, olaparib, synergistically enhances the activity of the CD33-targeted ADC, IMGN779, in preclinical AML models (Portwood S et al, ASH 2016). Based on the hypothesis that PARP inhibition will synergize with DNA damaging mechanism of IMGN632, we investigated the ability of olaparib and other PARP inhibitors (PARPi) in clinical development (talazoparib, niraparib, rucaparib, and veliparib) to enhance the therapeutic efficacy of IMGN632 across diverse human AML cell lines and primary relapsed/refractory AML samples. Materials and Methods CD123 expression on human AML cell lines (HEL, HL60, MV411, Molm13, EOL-1, THP-1, and Kasumi-1) was quantified by flow cytometry using QuantriBrite beads. AML cells were continuously cultured for 72-96 hours with varying doses of IMGN632 (range 100pM - 100nM) and specific PARP inhibitors (range 100pM -15μM) alone and in combination. Cell viability was measured using a WST-8 colorimetric assay. Primary clinically annotated CD123+ AML cells from patients with relapsed/refractory disease were obtained under IRB-approved protocols from the Roswell Park Hematologic Procurement Shared Resource and cultured short-term in the presence of multiple cytokines plus IMGN632 +/- PARP inhibitors. Apoptosis (Annexin V/PI), cell cycle, and DNA damage (H2AX) were evaluated by flow cytometry. Additive vs. synergistic effects were determined by combination indices using Compusyn software. PARP trapping was evaluated by Western blot analysis in nuclear lysates obtained from IMGN632 +/- PARP inhibitors treated AML cells. Results High expression levels of CD123 (range 937 - 2231 CD123 molecules/cell) were detected on multiple human AML cell lines (HEL-luc, MV411, Molm13, EOL-1, and THP-1) relative to unstained negative controls. Western blot analysis of nuclear lysates from AML cells demonstrated that all PARP inhibitors had varying degrees of PARP trapping on DNA. Continuous single agent 5-day treatment with all tested PARP inhibitors resulted in dose dependent in vitro inhibition of AML cell line growth with IC50 values ranging from 360 nM (talazoparib, most potent) to 78uM (veliparib, least potent). Combination therapy using PARP inhibitors (doses ranging from 300nM - 15uM) and IMGN632 (10nM) consistently resulted in enhanced anti-leukemic effects over monotherapy (Figure 1 for example). Synergistic anti-proliferative effects were obtained across all tested AML cell lines (n=5) with combination indexes ranging from 0.3-0.7 by Compusyn analysis. Combination therapy correlated with enhanced DNA damage, tumor cell apoptosis, and cell cycle arrest of AML cells. Moreover, IMGN632 and PARPi (olaparib or talazoparib) resulted in single agent activity against clinically annotated primary relapsed/refractory AML patient samples with evidence of synergistic effects when combined in vitro. Conclusions Addition of PARP inhibitors to IMGN632, a novel anti-CD123 antibody-drug conjugate, further enhances DNA damage effects and consistently results in synergistic in vitro anti-leukemic effects across multiple CD123+ AML cell lines and primary AML patient samples. Further studies investigating this novel combinatorial approach in specific molecular subtypes of AML with variable baseline sensitivities to PARPi are currently ongoing. Our results strongly support future investigation of PARPi as a novel class of agents with the potential to significantly enhance the efficacy of DNA-alkylating ADCs and/or cytotoxic chemotherapy for hematological malignancies. Figure. Figure. Disclosures Sloss: ImmunoGen: Employment. Watkins:ImmunoGen Inc.: Employment. Kovtun:ImmunoGen Inc.: Employment. Adams:ImmunoGen Inc.: Employment. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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