Target-Directed Development of a Proposed Biosimilar Rituximab (GP2013): Comparability of Antibody-Dependent Cellular Cytotoxicity Activity and Pre-Clinical Pharmacokinetics and Pharmacodynamics with Originator Rituximab

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4867-4867
Author(s):  
Antonio da Silva ◽  
Ulrich Kronthaler ◽  
Ines Meyer ◽  
Anastassia Papandrikopoulou ◽  
Thomas Stangler ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
B Cell Depletion ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Originator Product ◽  
Acceptance Range ◽  
Anti Tumor Activity

Abstract Abstract 4867 Background: Biosimilars are biologics approved by highly-regulated markets to be similar to existing agents that aim to offer more affordable treatment, thereby increasing patient access. Development of a biosimilar involves extensive characterization of the originator product over several years and a target-directed iterative development process to ensure a product that is highly comparable to the originator with similar clinical efficacy, safety and quality. Using antibody-dependent cellular cytotoxicity (ADCC), a main mode of action of rituximab, we illustrate how functional/structural relationship can be engineered into a biosimilar to ensure comparability at the in vitro level. Here we also present pre-clinical data confirming in vivo comparability for the proposed biosimilar rituximab GP2013, in terms of pharmacokinetics (PK), pharmacodynamics (PD) and efficacy. Methods: By employing a highly sensitive glycan quantitation method, relevant post-translational glycosylation patterns were assessed for their impact on in vitro ADCC relative potency data using the Raji and NK3.3 cell lines as target- and effector cells, respectively. Subsequently, bioactivity of GP2013 and originator rituximab were evaluated in a dose-response manner across a wide concentration range against SU-DHL-4 (diffuse large B-cell lymphoma) and Daudi (Burkitt's lymphoma) cell lines using freshly purified human NK cells. In vivo anti-tumor activity was assessed in two xenograft SCID mouse models of non-Hodgkin's lymphoma (SU-DHL-4 and Jeko-1 cell lines). Comparative PK and PD were assessed in single (5 mg/kg, n=14) and multiple (20 or 100 mg/kg, n=8) dose studies in cynomolgus monkeys, the pharmacologically most relevant species. Results: GP2013 and originator rituximab showed similar ADCC potency against both SU-DHL-4 and Daudi cells, with ADCC being reflective of engineered glycosylation patterns and structure-function relationships. In both xenograft mouse models, GP2013 and originator rituximab inhibited tumor growth to a similar extent, including at the more sensitive sub-optimal dose levels that are most likely to identify any potential differences. In primates, PK analysis confirmed bioequivalence between GP2013 and originator rituximab with nearly identical AUC values and 90% CIs entirely within the standard acceptance range of 0.8–1.25. Bioequivalence of PD response (B-cell depletion) was also shown, with 95% CIs of areas under the effect-time curves (AUEC) ratios for relative change from baseline in B-cell populations within the 0.8–1.25 acceptance range. The use of different doses indicated that comparable exposure and PD response can be expected for GP2013 and originator rituximab using indication-specific dosing regimens. Conclusions: This pre-clinical comparability exercise confirms that GP2013 and originator rituximab are pharmacologically similar with regard to ADCC potency, anti-tumor activity, PK exposure (AUC) and B-cell depletion. As such, it is hypothesized that GP2013 will show similar efficacy and safety as the originator product in ongoing clinical trials across different clinical indications. Disclosures: da Silva: Sandoz Biopharmaceuticals/HEXAL AG: Employment. Kronthaler:Sandoz Biopharmaceuticals/HEXAL AG: Employment. Meyer:Sandoz Biopharmaceuticals/HEXAL AG: Employment. Papandrikopoulou:Sandoz Biopharmaceuticals/HEXAL AG: Employment. Stangler:Sandoz Biopharmaceuticals/HEXAL AG: Employment. Visser:Sandoz Biopharmaceuticals/HEXAL AG: Employment.

Lenalidomide (Revlimid®) Enhances Monoclonal Antibody-Associated Anti-Tumor Activity Against Rituximab-Sensitive and Rituximab-Resistant B-Cell Lymphoma Cell Lines.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2522-2522 ◽  
Author(s):  
Nishitha Reddy ◽  
Raymond Cruz ◽  
Francisco Hernandez-Ilizaliturri ◽  
Joy Knight ◽  
Myron S. Czuczman
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Scid Mouse ◽  
In Vitro Exposure ◽  
Human Lymphoma ◽  
Scid Mouse Model ◽  
Anti Cd20 ◽  
Anti Tumor Activity

Abstract Background: Lenalidomide is a potent thalidomide analogue shown to activate both the innate and adoptive immune system, inhibit angiogenesis, and modify the tumor microenvironment. While lenalidomide has received approval by the U.S. Federal Drug Administration (FDA) for the treatment of various hematological conditions, ongoing clinical trials are addressing its role in the treatment of B-cell lymphomas. There is a dire need to develop novel well-tolerated, therapies which combine various target-specific agents such as lenalidomide and monoclonal antibodies (mAbs). We previously demonstrated that lenalidomide is capable of expanding natural killer (NK) cells in a human-lymphoma-bearing SCID mouse model and improve rituximab anti-tumor activity in vivo. Methods: In our current work we studied the effects of lenalidomide on the biological activity of a panel of mAbs against various B-cell lymphomas, utilizing various rituximab-sensitive (RSCL) and rituximab-resistant cell lines (RRCL) generated in our laboratory from Raji and RL cell lines. Functional assays including antibody-dependant cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) were performed to demonstrate changes in sensitivity to rituximab. RSCL and RRCL (1′105 cells/well) were exposed to either lenalidomide (5 μg/ml) or vehicle with or without mAb at a final concentration of 10μg/ml. The mAb panel consisted of two anti-CD20 mAbs: rituximab (Biogen IDEC, Inc.) and hA20, a humanized anti-CD20 mAb (Immunomedics, Inc.); an anti-CD80 mAb (galixumab, Biogen IDEC Inc.), and an anti-CD52 antibody (Alemtuzumab, Berlex Inc.). Changes in DNA synthesis and cell proliferation were determined at 24 and 48 hrs by [3H]-thymidine uptake. For ADCC/CMC studies, NHL cells were exposed to lenalidomide or vehicle for 24 hrs and then labeled with 51Cr prior to treatment with one of various mAbs (10 mg/ml) and peripheral blood mononuclear cells (Effector: Target ratio, 40:1) or human serum, respectively. 51Cr-release was measured and the percentage of lysis was calculated. Changes in antigen (CD20, CD80, and CD52) expression following in vitro exposure to lenalidomide were studied by multicolor flow cytometric analysis. Results: Concomitant in vitro exposure of various RSCL and RRCL cells to lenalidomide and either galixumab, hA20 or alemtuzumab for 24 hrs resulted in improved anti-tumor activity when compared to controls. In addition, pre-incubation of both RSCL and RRCL with lenalidomide rendered cells more susceptible to alemtuzumab-, hA20- and galixumab-mediated ADCC and CMC. No antigen modulation (i.e., upregulation) was observed following in vitro exposure of lenalidomide to NHL cell lines, suggesting an alternative mechanism involved in the improvement antitumor activity observed. Conclusions: Our data suggest that the augmented antitumor effect of lenalidomide is not limited to its combination with rituximab, but also that it augments the antiproliferative and biological activity of alemtuzumab, hA20 and galixumab. Furthermore, these interactions are observed even in our RRCL. Future studies will be directed towards evaluating whether similar activity will be seen in vivo using a human lymphoma-bearing SCID mouse model. (Supported by USPHS grant PO1-CA103985 from the National Cancer Institute.)

scholarly journals Development of CD19 CAR Engineered Human Placental CD34 +-Derived Natural Killer Cells (CAR19-CYNK) As an Allogeneic Cancer Immunotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2779-2779
Author(s):  
Marina Gergues ◽  
Irene Raitman ◽  
Joseph Gleason ◽  
Valentina Rousseva ◽  
Shuyang He ◽  
...  
Keyword(s):  
B Cell ◽  
Nk Cells ◽  
Cell Lines ◽  
B Cell Lymphoma ◽  
Publicly Traded ◽  
B Cell Malignancies ◽  
Cd34 Cells ◽  
Anti Tumor Activity

Abstract Background: Natural killer (NK) cells exhibit anti-tumor activity in a non-antigen-specific manner without causing graft-versus-host disease. T cell and cord blood NK cells expressing chimeric antigen receptor (CAR) targeting CD19 have demonstrated remarkable clinical efficacies against B cell lymphomas (Maude et al, N Engl J Med 2018; Neelapu et al, N Engl J Med 2017; Liu et al, N Engl J Med 2020). Celularity has developed a platform for the expansion and differentiation of human placental CD34 + stem cells towards NK cells. The introduction of CD19 CAR enables generation of CAR19-CYNK cells that can be used as an off-the-shelf, cryopreserved, allogeneic cell therapy for CD19 + B cell malignancies. Reported here are the in vitro and in vivo results evaluating anti-tumor activity of CAR19-CYNK against CD19 + B cell malignancies. Methods: CAR19-CYNK cells were generated by retroviral transduction of human placental CD34 + cells with an anti-CD19 CAR (CD19scFv-CD28CD3ζ, Sorrento Therapeutics), followed by culture expansion in the presence of cytokines. CD19 CAR expression and phenotype of CAR19-CYNK cells were characterized by flow cytometry using the following surface markers: CD56, CD3, CD226, CD16, CD11a, CD94, NKG2D, NKp30, NKp44, NKp46. The in vitro anti-tumor activity of CAR19-CYNK against the B cell lymphoma cell lines, Daudi and Nalm-6, was assessed at various effector to target (E:T) ratios using a flow cytometry-based cytotoxicity assay and multiplex Luminex analysis for cytokine profiling. Non-transduced (NT) NK cells were used as control. In vivo efficacy of CAR19-CYNK was assessed using a disseminated B-cell lymphoma xenograft model in B-NDG-hIL15 mice. B-NDG-hIL15 mice lack T, B, and NK cells and are transgenic for human IL-15 to support CAR19-CYNK persistence and maturation. Luciferase expressing Daudi cells (3×10 6) were intravenously (IV) injected on Day 0 three days after the mice were preconditioned with a myeloablative dose of busulfan to allow for better tumor cell engraftment. CAR19-CYNK cells (1x10 7) were IV injected on Day 7. Tumor burden was assessed weekly by bioluminescence imaging (BLI) and the mice were followed for assessment of their survival (n=5 mice per group). Results: Placental CD34 + cells were genetically modified using a retroviral vector and achieved an average of 29.2% ± 12.4% (range 17.5% to 50.1%; n=5 donor lots) CD19 CAR expression on CAR19-CYNK cells at the end of 35-day culture. The average fold expansion of CAR19-CYNK was 6186 ± 2847 with the range of 2692 to 10626 (n=5 donor lots). Post-thaw evaluation of CAR19-CYNK (n=5 donor lots) revealed 93.8 ± 3.9% of CD56 +CD3 - NK cells, and transduction of CD19 CAR on CYNK did not significantly alter NK cell phenotype based on various activation and lineage markers (CD226, CD16, CD11a, CD94, NKG2D, NKp30, NKp44, NKp46). CAR19-CYNK displayed enhanced in vitro cytotoxicity against lymphoma cell lines, Daudi and Nalm-6, compared to that of NT NK cells. At the E:T ratio of 10:1, CAR19-CYNK (n=5 donor lots) elicited significant increased cytotoxicity against Nalm-6 compared to that of NT NK cells, with 75.9 ± 14.8% vs. 0.00 ± 0.00% at 24h (p<0.005). Under the same condition, CAR19-CYNK (n=4 donor lots) showed higher cytotoxicity against Daudi compared to that of NT NK cells with 23.6 ± 18.9% vs. 4.9 ± 4.0%. When cocultured with tumor cell lines, CAR19-CYNK showed increased secretion of the proinflammatory cytokines GM-CSF (p<0.05 for both Nalm-6 and Daudi), IFN-g (p<0.05 for Nalm-6), and TNF-a compared to that of NT NK cells at an E:T ratio of 1:1 for 24h. To evaluate the in vivo efficacy of CAR19-CYNK, a disseminated Daudi xenograft B-NDG-hIL15 model was used. CAR19-CYNK treated mice demonstrated a significant survival benefit with a median survival of 39 days versus a median survival of 28 days for the vehicle treated group (p<0.05). Conclusions: In summary, we have successfully established a process for generating CAR19-CYNK cells from human placental CD34 + cells. CAR19-CYNK demonstrated enhanced in vitro cytotoxicity against CD19 + B cell malignancies and in vivo survival benefit in a disseminated lymphoma xenograft B-NDG-hIL15 model. Further development of CAR19-CYNK for CD19 + B cell malignancies is warranted. Disclosures Gergues: Celularity Inc: Current Employment, Current equity holder in publicly-traded company. Raitman: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Gleason: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Rousseva: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. He: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Van Der Touw: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Ye: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Kang: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: Sorrento Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Pai: Sorrento Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Guo: Sorrento Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Ji: Sorrento Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Hariri: Celularity Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: Celularity Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months.

Epratuzumab (Humanized Anti-CD22 MAb) Conjugated with SN-38, a New Antibody-Drug Conjugate (ADC) for the Treatment of Hematologic Tumors: Preclinical Studies Alone and In Combination with Veltuzumab, a Humanized Anti-CD20 MAb

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3941-3941
Author(s):  
David M Goldenberg ◽  
Serengulam Govindan ◽  
Tom M Cardillo ◽  
Robert M Sharkey
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cell ◽  
In Vivo Studies ◽  
Anti Cd20 ◽  
Anti Tumor Activity

Abstract Abstract 3941 Background: Monoclonal antibody (MAb) therapy has had a significant impact on the management of B-cell malignancies, but is most often used in combination with chemotherapy. We developed an ADC that combines SN-38, the active component of irinotecan, a topoisomerase I inhibitor, with the internalizing, humanized, anti-CD22 IgG, epratuzumab, and determined its activity alone and in combination with an anti-CD20 antibody therapy (veltuzumab). Methods: Epratuzumab was conjugated with SN-38 (E-SN-38) at a mole ratio of ∼6:1. The conjugate is designed specifically to be released slowly in the presence of serum (50% released over ∼1.5 days), allowing liberation of the drug when internalized, but also being released locally after being bound to the tumor. In vitro and in vivo studies were performed to assess the activity of the conjugate against several subcutaneously- or intravenously-inoculated B-cell lymphoma cell lines. In vivo studies also examined combination therapy using E-SN-38 and the veltuzumab (V). Results: In vitro studies in 4 B-cell lymphoma cells lines (Daudi, Raji, Ramos, WSU-FSCCL) and 4 acute lymphoblastic lymphoma cell lines (697, REH, MN-60, and RS4;11) expressing varying amounts of CD22 showed an IC50 for E-SN-38 in the nanomolar range, confirming potent activity. Nude mice bearing SC Ramos human lymphoma had significant selective anti-tumor activity compared to a control, non-targeting, IgG-SN-38 conjugate, at a dosing regimen of 75 to 250 μg of the conjugates given twice-weekly for 4 weeks. Significant anti-tumor activity was also found in several other cell lines. When combined with veltuzumab, significant improvement in therapeutic activity was observed. For example, median survival in a WSU-FSCCL human follicular B-cell lymphoma IV model with treatment initiated 5 days after implantation was 42 d (0/10 surviving at 160 d) and 91 d (2/10 surviving) for untreated and veltuzumab-treated animals, respectively; 63d (0/10 surviving after 160 d) and >160 d (with 6/10 surviving) for E-SN-38 and E-SN-38 + V, respectively; and 63 d (0/10) and 91 d (2/10) for non-targeting IgG-SN-38 conjugate alone and combined with V). The E-SN-38 conjugate combined with V was significantly better than all treatment or control groups (P ≤ 0.05). Conclusion: E-SN-38 ADC is a potent therapeutic, even at non-toxic dose levels, and shows significantly enhanced efficacy when combined with anti-CD20 immunotherapy, representing an important new ADC treatment regimen. Disclosures: Goldenberg: Immunomedics, Inc.: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Govindan:Immunomedics, Inc.: Employment. Cardillo:Immunomedics, Inc.: Employment.

B-1239, a Novel Anti-BAFF-R Afucosylated Human Antibody, Promotes Potent Natural Killer Cell- Mediated Antibody Dependent Cellular Cytotoxicity In Chronic Lymphocytic Leukemia Cells In- Vitro and Depletion Of Circulating Leukemic CLL B Cells In-Vivo

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4185-4185 ◽  
Author(s):  
Emily M. McWilliams ◽  
Carolyn Cheney ◽  
Jeffrey A. Jones ◽  
Joseph M. M. Flynn ◽  
Kami Maddocks ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cytotoxic Activity ◽  
Natural Killer ◽  
Lymphocytic Leukemia ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity

Abstract B-cell activating factor (BAFF) belongs to the TNF ligand superfamily of cytokines involved in B cell survival and maturation. BAFF is produced by diverse cell types including innate immune cells like monocytes and dendritic cells as well as T cells, activated B cells, and bone marrow stromal cells. BAFF binds to the BAFF receptor (BAFF-R) with high affinity compared to the other BAFF receptors, BCMA and TACI. While BAFF is known to regulate normal B-cell development and proliferation, it also contributes to survival in chronic lymphocytic leukemia (CLL). We observed expression of BAFF-R on virtually all B cells from CLL patients. B-CLL cells have strong up-regulation of BAFF and BAFF-R compared to normal healthy B cells. We describe here the in-vitro and in-vivo evaluation in CLL of B-1239, a fully human anti-BAFF-R monoclonal IgG1 antibody. B-1239 is devoid of fucose residues in its Fc domain, resulting in enhanced binding to FCgammaRIIIa activating receptor on Natural Killer (NK) cells. While B-1239 failed to induce direct or complement mediated cytotoxicity, binding of B-1239 to CLL cells resulted in enhanced antibody dependent cellular cytotoxicity (ADCC) with allogeneic or autologous NK effector cells in-vitro. Indeed, at a therapeutically relevant concentration of 10 ug/mL B-1239 shows more than 30% increased relative cytotoxic activity over current CLL antibody therapeutic Rituximab. Dilutions of B-1239 down to 0.01 ug/mL showed similar cytotoxicity to the 10 ug/mL concentration. At 0.0001 ug/mL B-1239 has a 40% cytotoxic effect on CLL cells in ADCC assays while antibody therapeutic controls, like Rituximab, show virtually no cytotoxic activity. Furthermore, B-1239 mediated antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages and mediated activation of monocytes and macrophages as detected by TNF-alpha production. Consistent with the cross reactivity to murine BAFF-R, flow cytometric analysis revealed binding of B-1239 to CD5+CD19+ leukemic B cells from Eu-Tcl-1 transgenic mouse CLL cells. A single dose of B-1239 by i.v injection into Eu-Tcl-1 mice resulted in dramatic reduction in circulating CD5+CD19+ leukemic B cells in all three B-1239 injected mice. In contrast, we observed continued increase of leukemic CD5+CD19+ populations in the two vehicle treated mice. Ongoing studies are focused on determining how targeting BAFF-R on CLL B-cells depletes the leukemic population both in-vitro and in-vivo and the downstream effects of targeting through this receptor. Collectively, these results demonstrate that targeting BAFF-R on CLL cells provides a B-cell specific approach for rapid and robust depletion of leukemic CLL cells and provides evidence for a strong therapeutic advantage in BAFF-R targeted therapies in CLL. Disclosures: Huet: Novartis: Employment, Employment Related Perks Other. Gram:Novartis: Employment, Employment Related Perks Other. Baeck:Novartis: Employment, Employment Related Perks Other.

Pre-Clinical Development of Adct-402, a Novel Pyrrolobenzodiazepine (PBD)-Based Antibody Drug Conjugate (ADC) Targeting CD19-Expressing B-Cell Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1564-1564 ◽  
Author(s):  
Francesca Zammarchi ◽  
David G. Williams ◽  
Lauren Adams ◽  
Karin Havenith ◽  
Simon Chivers ◽  
...  
Keyword(s):  
Single Dose ◽  
B Cell ◽  
Cell Lines ◽  
Xenograft Model ◽  
B Cell Malignancies ◽  
Employment Equity ◽  
Equity Ownership ◽  
Anti Tumor Activity

Abstract Human CD19 antigen is a 95 kilodalton type I transmembrane glycoprotein belonging to the immunoglobulin superfamily (Wang, Wei, & Liu, 2012). The role of CD19, both in health and disease, is well studied, and the therapeutic efficacy and safety of CD19 modulation have been well defined over several decades (Scheuermann & Racila, 1995). In normal human tissue, expression of CD19 is limited to the various stages of B-cell development and differentiation (except plasma cells) and its expression is maintained on the majority of B-cell malignancies, including B-cell leukemia and non-Hodgkin lymphomas of B-cell origin. CD19 has rapid internalization kinetics and it is not shed into the circulation (Blanc et al., 2011; Gerber et al., 2009). All these features make CD19 an attractive target for the development of an ADC to treat B-cell malignancies. ADCT-402 is an ADC composed of a humanized antibody directed against human CD19, stochastically conjugated via a valine-alanine cleavable, maleimide linker to a PBD dimer cytotoxin. PBD dimers are highly efficient anticancer drugs that covalently bind in the minor groove of DNA and form cytotoxic DNA interstrand cross-links. The average drug to antibody ratio of ADCT-402 is 2.3 ± 0.3, as shown by hydrophobic interaction chromatography and reverse-phase HPLC. In vitro, ADCT-402 demonstrated potent cytotoxicity in a panel of human-derived cell lines of differing levels of CD19, while its potency was strongly reduced in CD19-negative cell lines. In vivo, ADCT-402 demonstrated dose-dependent anti-tumor activity in a subcutaneously implanted human Burkitt's lymphoma-derived Ramos xenograft model, where a single dose at 0.33 mg/kg induced significantly delayed tumor growth compared to the vehicle-treated mice and at 0.66 mg/kg and 1 mg/kg gave 4/10 and 10/10 tumor-free survivors, respectively. In the same model, ADCT-402 showed remarkably superior anti-tumor activity compared to both maytansinoid- and auristatin-based CD19-targeting ADCs, when they were tested at the same dose and schedule (1 mg/kg, single dose). Moreover, ADCT-402 mediated an impressive increase in survival compared to both vehicle-treated and isotype control ADC-treated mice in the disseminated Ramos xenograft model when tested as a single dose at 0.33 mg/kg or 1 mg/kg. For example, a single dose of ADCT-402 at 1 mg/kg resulted in 10/10 survivors at day 91, while there were 0/10 survivors at day 19 in the group of animals treated with either the vehicle control or with a single dose of the non-binding, control ADC at 1 mg/kg. In rat, a single dose of ADCT-402 at 2 mg/kg was well tolerated with no adverse signs or hematologic effects. Altogether, these data show the potent and specific anti-tumor activity of ADCT-402 against CD19-expressing B-cell malignancies, both in vitro and in vivo, and warrant further development of this ADC into the clinic. Disclosures Zammarchi: ADC Therapeutics: Employment. Williams:Spirogen/Medimmune: Employment. Adams:Spirogen/Medimmune: Employment, Equity Ownership. Havenith:ADC Therapeutics: Employment. Chivers:ADC Therapeutics: Employment. D'Hooge:Spirogen/Medimmune: Employment, Equity Ownership. Howard:ADCT Spirogen/Medimmune: Employment, Equity Ownership, Patents & Royalties. Hartley:ADCT Spirogen/Medimmune: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. van Berkel:ADC Therapeutics: Employment, Equity Ownership, Patents & Royalties.

scholarly journals Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens

Haematologica ◽  
2019 ◽  
Vol 105 (4) ◽  
pp. 1032-1041 ◽  
Author(s):  
Anna Vidal-Crespo ◽  
Alba Matas-Céspedes ◽  
Vanina Rodriguez ◽  
Cédric Rossi ◽  
Juan G. Valero ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Anti Tumor Activity

scholarly journals Repurposing dasatinib for diffuse large B cell lymphoma

2019 ◽  
Vol 116 (34) ◽  
pp. 16981-16986 ◽  
Author(s):  
Claudio Scuoppo ◽  
Jiguang Wang ◽  
Mirjana Persaud ◽  
Sandeep K. Mittan ◽  
Katia Basso ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Multikinase Inhibitor ◽  
Large B Cell Lymphoma ◽  
Large B Cell

To repurpose compounds for diffuse large B cell lymphoma (DLBCL), we screened a library of drugs and other targeted compounds approved by the US Food and Drug Administration on 9 cell lines and validated the results on a panel of 32 genetically characterized DLBCL cell lines. Dasatinib, a multikinase inhibitor, was effective against 50% of DLBCL cell lines, as well as against in vivo xenografts. Dasatinib was more broadly active than the Bruton kinase inhibitor ibrutinib and overcame ibrutinib resistance. Tumors exhibiting dasatinib resistance were commonly characterized by activation of the PI3K pathway and loss of PTEN expression as a specific biomarker. PI3K suppression by mTORC2 inhibition synergized with dasatinib and abolished resistance in vitro and in vivo. These results provide a proof of concept for the repurposing approach in DLBCL, and point to dasatinib as an attractive strategy for further clinical development in lymphomas.

scholarly journals Establishment of B-Cell Lymphoma Cell Lines Persistently Infected with Hepatitis C Virus In Vivo and In Vitro: the Apoptotic Effects of Virus Infection

2003 ◽  
Vol 77 (3) ◽  
pp. 2134-2146 ◽  
Author(s):  
Vicky M.-H. Sung ◽  
Shigetaka Shimodaira ◽  
Alison L. Doughty ◽  
Gaston R. Picchio ◽  
Huong Can ◽  
...  
Keyword(s):  
Hepatitis C ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Culture System ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hcv Rna

ABSTRACT Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Studies of HCV replication and pathogenesis have so far been hampered by the lack of an efficient tissue culture system for propagating HCV in vitro. Although HCV is primarily a hepatotropic virus, an increasing body of evidence suggests that HCV also replicates in extrahepatic tissues in natural infection. In this study, we established a B-cell line (SB) from an HCV-infected non-Hodgkin's B-cell lymphoma. HCV RNA and proteins were detectable by RNase protection assay and immunoblotting. The cell line continuously produces infectious HCV virions in culture. The virus particles produced from the culture had a buoyant density of 1.13 to 1.15 g/ml in sucrose and could infect primary human hepatocytes, peripheral blood mononuclear cells (PBMCs), and an established B-cell line (Raji cells) in vitro. The virus from SB cells belongs to genotype 2b. Single-stranded conformational polymorphism and sequence analysis of the viral RNA quasispecies indicated that the virus present in SB cells most likely originated from the patient's spleen and had an HCV RNA quasispecies pattern distinct from that in the serum. The virus production from the infected primary hepatocytes showed cyclic variations. In addition, we have succeeded in establishing several Epstein-Barr virus-immortalized B-cell lines from PBMCs of HCV-positive patients. Two of these cell lines are positive for HCV RNA as detected by reverse transcriptase PCR and for the nonstructural protein NS3 by immunofluorescence staining. These observations unequivocally establish that HCV infects B cells in vivo and in vitro. HCV-infected cell lines show significantly enhanced apoptosis. These B-cell lines provide a reproducible cell culture system for studying the complete replication cycle and biology of HCV infections.

A Humanized Anti-Ganglioside GM2 Antibody, BIW-8962, Exhibits ADCC/CDC Activity against Multiple Myeloma Cells and Potent Anti- Tumor Activity in Mouse Xenograft Models.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1718-1718 ◽  
Author(s):  
Toshihiko Ishii ◽  
Asher Alban Chanan-Khan ◽  
Jazur Jafferjee ◽  
Noreen Ersing ◽  
Takeshi Takahashi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Phase 1 ◽  
Xenograft Model ◽  
Surface Expression ◽  
Scid Mice ◽  
Subcutaneous Xenograft ◽  
Anti Tumor Activity

Abstract BIW-8962 is a humanized anti-ganglioside GM2 (GM2) monoclonal antibody, produced by Poteligent technology to enhance ADCC activity. GM2 is expressed on many cancer cells including multiple myeloma (MM), small cell lung cancer and glioma cells. In this study, we evaluated the anti-myeloma activity of BIW-8962 in preclinical myeloma models both in vitro and in vivo. Expression of GM2 was analyzed in 15 human MM cell lines by FCM. Eleven out of 15 MM cell lines had positive surface expression of GM2. GM2 as a potential target was then verified in primary MM samples obtained from patients. Eleven out of 15 samples were positive for GM2. We then used two GM2 positive MM cell lines (U266B1 and KMS-11) and evaluated ADCC and CDC activity of BIW-8962 in vitro. BIW-8962 exhibited a potent ADCC and less potent CDC activity. In vivo anti-tumor activity of BIW-8962 was then examined using the standard subcutaneous xenograft model; KMS-11 was inoculated in the flank of SCID mice. BIW-8962 (intravenously administered biweekly for 3 weeks) exhibited a potent anti-tumor activity from as low a dose level as 0.1 mg/kg. Furthermore, in a more clinically relevant model, in which OPM-2/GFP (GM2 positive MM cell line) cells were intravenously inoculated into SCID mice with preferentially tumor growth within the bone marrow microenvironment, BIW-8962 (intravenously administered biweekly for 4 weeks, 10 mg/kg) suppressed OPM-2/GFP cell growth and serum M protein elevation, demonstrating in vivo anti-myeloma effect of BIW-8962. Our preclinical investigations rationalize clinical evaluation of BIW-8962 in patients with MM. Currently BIW-8962 is being investigated in a Phase 1 study in patients with multiple myeloma.

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