Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies

Blood ◽  
2010 ◽  
Vol 116 (16) ◽  
pp. 3004-3012 ◽  
Author(s):  
Holly M. Horton ◽  
Matthew J. Bernett ◽  
Matthias Peipp ◽  
Erik Pong ◽  
Sher Karki ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Hematologic Malignancies ◽  
Myeloma Cell ◽  
Neoplastic Disease ◽  
Primary Tumors ◽  
Multiple Myeloma Cell ◽  
In Vivo Antitumor Activity

AbstractCD40 is highly expressed on various B-lineage malignancies and represents an attractive immunotherapy target for neoplastic disease. Previous work showed that engineering the Fc domain of an antibody for increased binding to Fcγ receptors (FcγRs) significantly enhanced Fc-mediated immune effector function and antitumor activity in vitro and in vivo. We developed a humanized anti-CD40 antibody similarly Fc-engineered for increased FcγR binding (XmAbCD40) and compared its efficacy with that of an anti-CD40 native IgG1 analog and the anti-CD20 antibody rituximab. XmAbCD40 increased antibody-dependent cell-mediated cytotoxicity (ADCC) up to 150-fold relative to anti-CD40 IgG1 against B-lymphoma, leukemia, and multiple myeloma cell lines, and significantly enhanced ADCC against primary tumors. XmAbCD40 was also superior to rituximab in enhancing ADCC (both in cell lines and primary tumors) and in augmenting antibody-dependent cellular phagocytosis. XmAbCD40 significantly inhibited lymphoma growth in disseminated and established mouse xenografts and was more effective than the IgG1 analog or rituximab. An anti-CD40 antibody constructed to abrogate FcγR binding showed no reduction of tumor growth, indicating that the in vivo antitumor activity of XmAbCD40 is primarily mediated via FcγR-dependent mechanisms. These data demonstrate that XmAbCD40 displays potent antitumor efficacy and merits further evaluation for the treatment of CD40+ malignancies.

„IN VITRO“ AND „IN VIVO“ ANTITUMOR ACTIVITY OF PLATINUM(II) COMPLEXES WITH MALONIC ACID ON BREAST AND COLORECTAL CARCINOMA CELL LINES

2021 ◽  
Author(s):  
Andjela Franich ◽  
◽  
Milica Dimitrijević Stojanović ◽  
Snežana Rajković ◽  
Marina Jovanović ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Colorectal Carcinoma ◽  
Cell Lines ◽  
Tumor Model ◽  
Carcinoma Cells ◽  
Spectroscopic Techniques ◽  
Murine Cell Line ◽  
In Vivo Antitumor Activity

Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is anion of malonic (mal, Pt1), 2-methylmalonic (Me-mal, Pt2), 2,2-dimethylmalonic (Me2-mal, Pt3) or 1,1- cyclobutanedicarboxylic (CBDCA, Pt4) acid while 5,6-epoxy-1,10-phen is bidentately coordinated 5,6-epoxy-5,6-dihydro-1,10-phenanthroline were synthesized and characterized by elemental microanalysis, IR, UV-Vis and NMR (1H and 13C) spectroscopic techniques. In vitro anticancer activity of novel platinum(II) complexes have been investigated on human and murine cancer cell lines, as well as normal murine cell line by MTT assay. The obtained results indicate that studied platinum(II) complexes exhibited strong cytotoxic activity against murine breast carcinoma cells (4T1), human (HCT116) and murine (CT26) colorectal carcinoma cells. Complex Pt3 display stronger selectivity toward carcinoma cells in comparison to other tested platinum(II) complexes exhibiting beneficial antitumor activity mainly via the induction of apoptosis, as well as inhibition of cell proliferation and migration. Further study showed that Pt3 complex also carry significant in vivo antitumor activity in orthotopical 4T1 tumor model without detected liver, kidney, lung, and heart toxicity. All results imply that these novel platinum(II) complexes have a good anti-tumor effect on breast and colorectal cancer in vivo and in vitro and the affinity to become possible candidates for treatment in anticancer therapy.

scholarly journals Targeted Brain Tumor Therapy by Inhibiting the MDM2 Oncogene: In Vitro and In Vivo Antitumor Activity and Mechanism of Action

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1592
Author(s):  
Surendra R. Punganuru ◽  
Viswanath Arutla ◽  
Wei Zhao ◽  
Mehrdad Rajaei ◽  
Hemantkumar Deokar ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Tumor Therapy ◽  
Single Agent ◽  
M Cell ◽  
In Vivo Antitumor Activity ◽  
The Brain

There is a desperate need for novel and efficacious chemotherapeutic strategies for human brain cancers. There are abundant molecular alterations along the p53 and MDM2 pathways in human glioma, which play critical roles in drug resistance. The present study was designed to evaluate the in vitro and in vivo antitumor activity of a novel brain-penetrating small molecule MDM2 degrader, termed SP-141. In a panel of nine human glioblastoma and medulloblastoma cell lines, SP-141, as a single agent, potently killed the brain tumor-derived cell lines with IC50 values ranging from 35.8 to 688.8 nM. Treatment with SP-141 resulted in diminished MDM2 and increased p53 and p21cip1 levels, G2/M cell cycle arrest, and marked apoptosis. In intracranial xenograft models of U87MG glioblastoma (wt p53) and DAOY medulloblastoma (mutant p53) expressing luciferase, treatment with SP-141 caused a significant 4- to 9-fold decrease in tumor growth in the absence of discernible toxicity. Further, combination treatment with a low dose of SP-141 (IC20) and temozolomide, a standard anti-glioma drug, led to synergistic cell killing (1.3- to 31-fold) in glioma cell lines, suggesting a novel means for overcoming temozolomide resistance. Considering that SP-141 can be taken up by the brain without the need for any special delivery, our results suggest that SP-141 should be further explored for the treatment of tumors of the central nervous system, regardless of the p53 status of the tumor.

scholarly journals In Vitro and in Vivo Antitumor Activity of Scutebarbatine A on Human Lung Carcinoma A549 Cell Lines

Molecules ◽  
2014 ◽  
Vol 19 (7) ◽  
pp. 8740-8751 ◽  
Author(s):  
Xiao-Kun Yang ◽  
Ming-Yuan Xu ◽  
Gui-Sen Xu ◽  
Yu-Lan Zhang ◽  
Zhao-Xia Xu
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Lung Carcinoma ◽  
A549 Cell ◽  
Human Lung ◽  
In Vivo Antitumor Activity ◽  
Human Lung Carcinoma

Constitutive and Immunoproteasome Inhibitors Increase IκB and Decrease NF-κB Expression In Dendritic Cell

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3493-3493
Author(s):  
Ahmad-Samer Samer Al-Homsi ◽  
Zhongbin Lai ◽  
Tara Sabrina Roy ◽  
Niholas Kouttab
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Cell Lines ◽  
Mechanism Of Action ◽  
Peripheral Blood ◽  
Research Funding ◽  
Myeloma Cell ◽  
Multiple Myeloma Cell

Abstract Introduction Constitutive and immunoproteasome inhibitors (C&IPI) were thought to suppress nuclear factor-κB (NF-κB) pathway by preventing IκB degradation, which prevents NF-κB translocation into the nucleus. This mechanism of action has since been questioned by a number of studies. First, bortezomib promoted constitutive NF-κB activity in endothelial cell carcinoma. Second, NF-κB constitutive activity was resistant to bortezomib in multiple myeloma cell lines. Third, bortezomib increased IκB mRNA but post-transcriptionally downregulated IκB in normal cells and in multiple myeloma cell lines resulting in induced canonical NF-κB activation. Lastly, bortezomib increased nuclear levels of IκB as opposed to lowering cytoplasmic levels in cutaneous T cell lymphoma cell line suggesting that nuclear translocation of IκB was possibly responsible for NF-κB inhibition. The inhibitory activity of C&IPI on dendritic cells (DC) is of interest in the prevention of graft versus host disease (GvHD). It has been shown that different C&IPI impede DC maturation and T cell priming both in vitro and in vivo. Herein we sought to understand the mechanism of action of proteasome and immunoproteasome inhibitors on DC and to test their effect on IκB and NF-IκB expression. Materials and Methods We first performed RT PCR on lysates of DC obtained from the peripheral blood of 7 patients who received post-transplant cyclophosphamide and bortezomib as prevention of GvHD on a phase I clinical trial. Patients received allogeneic transplantation from matched-related or unrelated donors. Patients received no other immunosuppressive therapy except for rabbit anti-thymocyte globulin for those receiving graft from unrelated donor. Steroids were not allowed on the study. Samples were obtained on days +1, +4, and +7. The results were analyzed in comparison to samples obtained on day 0 before stem cell infusion. We then performed the same experiment on lysates of DC obtained from the peripheral blood of healthy volunteer donors. DC were untreated or incubated with bortezomib (10 nM for 4 h), carfilzomib (30 nM for 1 h), oprozomib (100 nM and 300 nM for 4 h), ONX 0914 (200 nM for 1 h), PR-825 (125 nM for 1 h), or PR-924 (1000 nM for 1 h). The drug concentration and duration of exposure were chosen based on the IC50 on proteasome activity and to reproduce in vivo conditions. We also performed IκB western blot on DC isolated from peripheral blood of healthy volunteers, untreated or incubated with bortezomib (10 nM for 4 h) or oprozomib (300 nM for 4 h). Each experiment was performed at least in triplicate. Results We found that the combination of cyclophosphamide and bortezomib significantly and progressively increased IκB mRNA while decreasing NF-κB mRNA in DC studied ex vivo. We also found that all studied C&IPI increased IκB mRNA to a variable degree while only oprozomib (300 nM) decreased NF-κB mRNA in DC in vitro. Finally, both bortezomib and oprozomib increased IκB protein level in DC in vitro (figure). Conclusion Our data suggest that C&IPI increase IκB expression in DC. As opposed to the previously reported data in other cell types, the effect is not associated with post-transcriptional downregulation. Cyclophosphamide and bortezomib also decrease NF-κB expression in DC in vivo while only oprozomib had the same effect in vitro. The effect of C&IPI on IκB and NF-κB expression may represent a new mechanism of action and suggests their effect may be cell-type dependent. Disclosures: Al-Homsi: Millennium Pharmaceuticals: Research Funding. Off Label Use: The use of cyclophosphamide and bortezomib for GvHD prevention. Lai:Millennium Pharmaceuticals: Research Funding.

Cytotoxic activity of the maytansinoid immunoconjugate B-B4–DM1 against CD138+ multiple myeloma cells

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3688-3696 ◽  
Author(s):  
Pierfrancesco Tassone ◽  
Victor S. Goldmacher ◽  
Paola Neri ◽  
Antonella Gozzini ◽  
Masood A. Shammas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Fluorescent Protein ◽  
Scid Mice ◽  
Dependent Manner ◽  
In Vivo Antitumor Activity ◽  
Mouse Tissues

We tested the in vitro and in vivo antitumor activity of the maytansinoid DM1 (N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine), a potent antimicrotubule agent, covalently linked to the murine monoclonal antibody (mAb) B-B4 targeting syndecan-1 (CD138). We evaluated the in vitro activity of B-B4–DM1 against a panel of CD138+ and CD138- cell lines, as well as CD138+ patient multiple myeloma (MM) cells. Treatment with B-B4–DM1 selectively decreased growth and survival of MM cell lines, patient MM cells, and MM cells adherent to bone marrow stromal cells. We further examined the activity of B-B4–DM1 in 3 human MM models in mice: (1) severe combined immunodeficient (SCID) mice bearing subcutaneous xenografts; (2) SCID mice bearing green fluorescent protein–positive (GFP+) xenografts; and (3) SCID mice implanted with human fetal bone (SCID-hu) and subsequently injected with patient MM cells. Tumor regression and inhibition of tumor growth, improvement in overall survival, and reduction in levels of circulating human paraprotein were observed in mice treated with B-B4–DM1. Although immunohistochemical analysis demonstrates restricted CD138 expression in human tissues, the lack of B-B4 reactivity with mouse tissues precludes evaluation of its toxicity in these models. In conclusion, B-B4–DM1 is a potent anti-MM agent that kills cells in an antigen-dependent manner in vitro and mediates in vivo antitumor activity at doses that are well tolerated, providing the rationale for clinical trials of this immunoconjugate in MM.

scholarly journals The Mucolipin TRPML2 Channel Enhances the Sensitivity of Multiple Myeloma Cell Lines to Ibrutinib and/or Bortezomib Treatment

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 107
Author(s):  
Giorgio Santoni ◽  
Consuelo Amantini ◽  
Federica Maggi ◽  
Oliviero Marinelli ◽  
Matteo Santoni ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Biological Effects ◽  
Myeloma Cell ◽  
Multiple Myeloma Cell ◽  
Bortezomib Treatment

Multiple myeloma (MM) is a haematological B cell malignancy characterised by clonal proliferation of plasma cells and their accumulation in the bone marrow. The aim of the present study is the evaluation of biological effects of Ibrutinib in human MM cell lines alone or in combination with different doses of Bortezomib. In addition, the relationship between the expression of TRPML2 channels and chemosensitivity of different MM cell lines to Ibrutinib administered alone or in combination with Bortezomib has been evaluated. By RT-PCR and Western blot analysis, we found that the Ibrutinib-resistant U266 cells showed lower TRPML2 expression, whereas higher TRPML2 mRNA and protein levels were evidenced in RPMI cells. Moreover, TRPML2 gene silencing in RPMI cells markedly reverted the effects induced by Ibrutinib alone or in combination with Bortezomib suggesting that the sensitivity to Ibrutinib is TRPML2 mediated. In conclusion, this study suggests that the expression of TRPML2 in MM cells increases the sensitivity to Ibrutinib treatment, suggesting for a potential stratification of Ibrutinib sensitivity of MM patients on the basis of the TRPML2 expression. Furthermore, studies in vitro and in vivo should still be necessary to completely address the molecular mechanisms and the potential role of TRPML2 channels in therapy and prognosis of MM patients.

scholarly journals Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1838
Author(s):  
Naglaa M. Ahmed ◽  
Mahmoud M. Youns ◽  
Moustafa K. Soltan ◽  
Ahmed M. Said
Keyword(s):  
Molecular Modeling ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Antitumor Agents ◽  
Cancer Cell Lines ◽  
Normal Cells

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79 %) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

Synthesis, in vitro and in vivo antitumor activity of symmetrical bis-Schiff base derivatives of isatin

2014 ◽  
Vol 74 ◽  
pp. 742-750 ◽  
Author(s):  
Chengyuan Liang ◽  
Juan Xia ◽  
Dong Lei ◽  
Xiang Li ◽  
Qizheng Yao ◽  
...  
Keyword(s):  
Schiff Base ◽  
Antitumor Activity ◽  
Schiff Base Derivatives ◽  
In Vivo Antitumor Activity ◽  
Derivatives Of

Simvastatin Induces Death of Multiple Myeloma Cell Lines

2004 ◽  
Vol 52 (5) ◽  
pp. 335-344 ◽  
Author(s):  
Naomi Gronich ◽  
Liat Drucker ◽  
Hava Shapiro ◽  
Judith Radnay ◽  
Shai Yarkoni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Cytoplasmic Calcium ◽  
Multiple Myeloma Cell ◽  
Cycle Arrest ◽  
Rpmi 8226

BackgroundAccumulating reports indicate that statins widely prescribed for hypercholesteromia have antineoplastic activity. We hypothesized that because statins inhibit farnesylation of Ras that is often mutated in multiple myeloma (MM), as well as the production of interleukin (IL)-6, a key cytokine in MM, they may have antiproliferative and/or proapoptotic effects in this malignancy.MethodsU266, RPMI 8226, and ARH77 were treated with simvastatin (0-30 μM) for 5 days. The following aspects were evaluated: viability (IC50), cell cycle, cell death, cytoplasmic calcium ion levels, supernatant IL-6 levels, and tyrosine kinase activity.ResultsExposure of all cell lines to simvastatin resulted in reduced viability with IC50s of 4.5 μM for ARH77, 8 μM for RPMI 8226, and 13 μM for U266. The decreased viability is attributed to cell-cycle arrest (U266, G1; RPMI 8226, G2M) and cell death. ARH77 underwent apoptosis, whereas U266 and RPMI 8226 displayed a more necrotic form of death. Cytoplasmic calcium levels decreased significantly in all treated cell lines. IL-6 secretion from U266 cells was abrogated on treatment with simvastatin, whereas total tyrosine phosphorylation was unaffected.ConclusionsSimvastatin displays significant antimyeloma activity in vitro. Further research is warranted for elucidation of the modulated molecular pathways and clinical relevance.

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