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.

scholarly journals Targeting CD205 with the antibody drug conjugate MEN1309/OBT076 is an active new therapeutic strategy in lymphoma models

Haematologica ◽  
2020 ◽  
Vol 105 (11) ◽  
pp. 2584-2591 ◽  
Author(s):  
Eugenio Gaudio ◽  
Chiara Tarantelli ◽  
Filippo Spriano ◽  
Francesca Guidetti ◽  
Giulio Sartori ◽  
...  
Keyword(s):  
Cell Lines ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Antibody Drug Conjugate ◽  
In Vivo Models ◽  
Drug Conjugate ◽  
Anti Tumor Activity ◽  
Class Antibody ◽  
Antibody Drug

Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematological cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class antibody drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leukemias and multiple myeloma by immunohistochemistry on tissue microarrays. Anti-tumor activity of MEN1309/OBT076 as single agent was then shown across 42 B-cell lymphoma cell lines with a median IC50 of 200 pM and induction of apoptosis in 25/42 (59.5%) of the cases. The activity appeared highly correlated with its target expression. After in vivo validation as the single agent, the antibody drug conjugate synergized with the BCL2 inhibitor venetoclax, and the anti-CD20 monoclonal antibody rituximab. The first-in-class antibody drug targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti-tumor activity in lymphoma, warranting further investigations as a single agent and in combination.

Novel Fc-Engineered Anti-B Cell Maturation Antigen-Monomethyl Auristatin F Antibody-Drug Conjugate (GSK2857916) Induces Potent and Selective Anti-Multiple Myeloma Activity Via Enhanced Effector Function and Direct Tumor Cell Killing

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 877-877
Author(s):  
Yu-Tzu Tai ◽  
Chirag Acharya ◽  
Mike Y Zhong ◽  
Michele Cea ◽  
Antonia Cagnetta ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Cell Maturation ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
B Cell Maturation ◽  
Equity Ownership ◽  
B Cell Maturation Antigen ◽  
Antibody Drug

Abstract B cell maturation antigen (BCMA), which is highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). We here investigated the anti-MM activity of J6M0-mcMMAF (GSK2857916), a humanized and afucosylated anti-BCMA antibody-drug conjugate (ADC) via uncleavable linker. This novel antagonist anti-BCMA antibody shows binding against all CD138-expressing MM cell lines (n=13) and patient MM cells (n=18), confirming universal BCMA expression on the surface of myeloma cells. Real-time qRT-PCR also showed significantly upregulated BCMA mRNA in CD138+ cells purified from MM patients vs. normal donors (p < 0.03). In contrast, BCMA is undetectable in CD138-negative cells from MM patients (n=3). J6M0-mcMMAF strongly blocks cell growth and induces caspase 3-dependent apoptosis in both drug-sensitive and -resistant MM cell lines and patient CD138+ MM cells, alone and in co-culture with BMSCs. In contrast, an isotype control antibody-drug conjugate (iso-mcMMAF) had no effect on viability of ANBL6 MM cells, alone or cocultured with BMSC. J6M0-mcMMAF specifically induces cell death in CD138-positive patient MM cells but not CD138-negative cells, demonstrating the minimal bystander killing against surrounding BCMA-negative cells. J6M0-mcMMAF completely blocks colony formation of MM cell lines (n=6) via induction of G2/M arrest, followed by apoptosis. This ADC does not affect viability of BCMA-negative NK, PBMC, and BMSCs, cultured alone or together, confirming its specific targeting of BCMA-positive MM cells. J6M0-mcMMAF, which has enhanced Fc-receptor binding due to afucosylation, significantly improved autologous antibody-dependent cellular cytotoxicity (ADCC) potency and maximum MM cell lysis against MM patient cells (n=5), when compared to J6M0 with normal Fc. Such augmented ADCC and maximum patient MM cell lysis by J6M0-mcMMAFis more pronounced in the autologous setting vs. the allogenic setting where MM cells and healthy donor effectors were used. Pretreatment of PBMC effector cells with lenalidomide further increased J6M0-mcMMAF-induced ADCC against MM cells in the presence or absence of BMSC. The in vivo efficacy of J6M0-mcMMAF was evaluated in murine subcutaneous xenograft models using NCI-H929 and OPM2 cells, as well as in NK-deficient SCID-beige mice with diffuse human MM bone lesions using MM1Sluc cells. Administration of J6M0-mcMMAF at 4 mg/kg (q3d x 4, ip) completely eliminated NCI-H929 and OPM2 xenograft tumors in all mice which remained tumor-free until the termination of studies at 60 and 100 days, respectively. In the MM1Sluc bone marrow dissemination model, J6M0-mcMMAF eradicates detectable tumors after 2 doses at 0.4 mg/kg (q3d x 9, ip), which resulted in extended survival (p<0.0001) and no weight loss of mice following 120 days. J6M0 treatment, although less effective than J6M0-mcMMAF, also had significantly prolonged survival (p<0.03) and diminished tumor burden when compared with control vehicle and isotype-treated groups, indicating a potential role of macrophage-mediated phagocytosis. Indeed, J6M0-mcMMAF recruits macrophage and mediates phagocytosis of target MM cells. Taken together, our studies show that J6M0-mcMMAF potently and selectively induce direct and indirect killing of MM tumor cells both in vitro and in vivo, providing a very promising next-generation immunotherapeutic in this cancer. Disclosures: Tai: Onyx: Consultancy. Mayes:GlaxoSmithKline: Employment. Craigen:GlaxoSmithKline: Employment. Gliddon:GlaxoSmithKline: Employment. Smothers:GlaxoSmithKline: Employment. Richardson:Millenium: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Munshi:Celgene: Consultancy; Novartis: Consultancy; Millennium: Consultancy. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership.

scholarly journals Novel Antibody-Drug Conjugate with Anti-CD26 Humanized Monoclonal Antibody and Transcription Factor IIH (TFIIH) Inhibitor, Triptolide, Inhibits Tumor Growth via Impairing mRNA Synthesis

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1138 ◽  
Author(s):  
Hayashi ◽  
Madokoro ◽  
Yamada ◽  
Nishida ◽  
Morimoto ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Cell Lines ◽  
Mrna Synthesis ◽  
Antibody Drug Conjugate ◽  
Pol Ii ◽  
Drug Conjugate ◽  
Antibody Drug

Here, we report a novel antibody drug conjugate (ADC) with the humanized anti-CD26 monoclonal antibody YS110 and triptolide (TR-1). YS110 has an inhibitory activity against the CD26-positive tumor growth via the immunological and direct pathway, such as intra-nuclear transportation of CD26 and YS110, and suppressed transcription of RNA polymerase II (Pol II) subunit POLR2A. The ADC conjugated with YS110 and an antitumor compound triptolide (TR-1), which is an inhibitor for TFIIH, one of the general transcription factors for Pol II was developed. YS110 and triptolide were crosslinked by the heterobifunctional linker succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) and designated Y-TR1. Antitumor efficacy of Y-TR1 against malignant mesothelioma and leukemia cell lines were assessed by the in vitro cell viability assay and in vivo assay using xenografted mouse models. Y-TR1 showed significant cytotoxicity against CD26-positive cell lines but not CD26-negative counterparts in a dose-dependent manner via suppression of mRNA synthesis by impairment of the Pol II activity. The tumors in xenografted mice administered Y-TR1 was smaller than that of the unconjugated YS110 treated mice without severe toxicity. In conclusion, the novel compound Y-TR1 showed antitumor properties against CD26-positive cancer cell lines both in vitro and in vivo without toxicity. The Y-TR1 is a unique antitumor ADC and functions against Pol II.

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

Axially-substituted silicon phthalocyanine payloads for antibody-drug conjugates

Synlett ◽  
2021 ◽  
Author(s):  
Kazuki Takahashi ◽  
Akira Sugiyama ◽  
Kei Ohkubo ◽  
Toshifumi Tatsumi ◽  
Tatsuhiko Kodama ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Antibody Drug Conjugate ◽  
Antibody Drug Conjugates ◽  
Drug Conjugate ◽  
Drug Conjugates ◽  
Antibody Drug ◽  
Silicon Phthalocyanine

IR700, a silicon phthalocyanine (SiPc) photosensitizer, is an antibody-drug conjugate payload used clinically. It is, however, the sole SiPc payload to date, possibly due to the difficulty of its synthesis, resulting from its asymmetric phathalocyanine skeleton. Here we report a new axially-substituted SiPc payload with easier synthesis. Trastuzumab conjugated with the SiPc showed light- and antigen-dependent cytotoxicity in HER2-overexpressed cancer cell lines.

scholarly journals LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 757 ◽  
Author(s):  
Eytan Ben-Ami ◽  
Raul Perret ◽  
Ying Huang ◽  
Félicie Courgeon ◽  
Prafulla C. Gokhale ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Stromal Cells ◽  
Soft Tissue Sarcomas ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
In Vivo Experiments ◽  
Patient Derived Xenograft ◽  
Pdx Models ◽  
Antibody Drug

Background: LRRC15 is a member of the LRR (leucine-rich repeat) superfamily present on tumor-associated fibroblasts (CAFs) and stromal cells. The expression of LRRC15 is upregulated by the pro-inflammatory cytokine TGFβ. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target LRRC15, and which has shown significant anti-tumor activity in several tumor models. This is the first focused examination of LRRC15 expression and ABBV-085 activity in soft-tissue sarcomas (STS). Methods: We analyzed the LRRC15 expression profile by immunohistochemistry in 711 STS cases, covering a broad spectrum of STS histologies and sub-classifications. In vivo experiments were carried out by using LRRC15-positive and LRRC15-negative patient-derived xenograft (PDX) models of STS. Results: In contrast to patterns observed in epithelial tumors, LRRC15 was expressed not only by stromal cells but also by cancer cells in multiple subsets of STS with significant variations noted between histological subtypes. Overexpression of LRRC15 is positively correlated with grade and independently associated with adverse outcome. ABBV-085 has robust preclinical efficacy against LRRC15 positive STS patient-derived xenograft (PDX) models. Conclusion: We provide the first preclinical evidence that LRRC15 targeting with an antibody-drug conjugate is a promising strategy in LRRC15-positive STS. ABBV-085 is being evaluated in an ongoing clinical trial in STS and other malignancies.

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