Human angiogenin fused to human CD30 ligand (Ang-CD30L) exhibits specific cytotoxicity against CD30-positive lymphoma

Hühn, Michael; Sasse, Stephanie; Tur, Mehmet Kemal; Schinköthe, Timo; Rybak, Susanna M.; Engert, Andreas; Barth, Stephanie

doi:10.1016/s0959-8049(01)80351-8

Cited by 43 publications

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“…Antibody-based chemoimmunotherapy is among the most promising, novel treatment strategies. 43 In the alternative, standard or reduced-intensity allogeneic transplantation may be investigated, at least in younger patients who have a human lymphocyte antigen-compatible donor. 44,45 Presentation with B symptoms also was predictive of a poor outcome in the current study, similar to other reports, 10,18,19 whereas none of the other clinical features that were proposed as strong predictors of outcome (i.e., age, disease stage, bulky disease, BM or other extralymph node involvement, and duration of first CR) were significantly prognostic.…”

Section: Discussionmentioning

confidence: 99%

High‐dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma

Tarella

Cuttica

Vitolo

et al. 2003

Cancer

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BACKGROUNDThe objective of the current study was to evaluate in a multicenter setting the feasibility and efficacy of a high‐dose sequential (HDS) chemotherapy regimen that combined intensive debulking and high‐dose therapy (HDT) with peripheral blood progenitor cell (PBPC) autografting in patients with refractory or recurrent Hodgkin lymphoma (HL).METHODSData were collected from 102 patients with HL who were treated with the HDS regimen at 14 centers associated with the Intergruppo Italiano Linfomi. Twenty‐four patients had primary refractory HL, 59 patients had their first recurrence of HL (within 1 year in 32 patients and > 1 year in 27 patients), and 19 patients had multiple disease recurrences. The HDS regimen included the sequential delivery of high‐dose (hd) cyclophosphamide with PBPC harvesting, methotrexate, etoposide, then HDT (usually hd mitoxantrone plus L‐phenylalanine mustard) with PBPC autografting. In addition, radiotherapy was delivered to 36 patients at sites of bulky or persistent disease.RESULTSNinety‐two patients (90%) completed the HDS program. There were five toxic deaths (treatment‐related mortality rate, 4.9%) and six secondary malignan cies (five patients developed myelodysplastic syndrome/acute myelogenous leukemia, and one patient developed colorectal carcinoma). At a median follow‐up of 5 years, the 5‐year overall survival (OS) and event‐free survival (EFS) projections were 64% (95% confidence interval [95% CI], 54–74%) and 53% (95% CI, 43–63%), respectively. Patients with their first recurrence had the most favorable outcome, with 5‐year OS and EFS projections of 77% (95% CI, 66–88%) and 63% (95% CI, 50–76%), respectively. There were no significant differences between patients with early first recurrence and late first recurrence. The poorest outcome was observed in patients with refractory HL, with 5‐year OS and EFS projections of 36% (95% CI, 16–55%) and 33% (95% CI, 14–52%), respectively. Patients who received HDS chemotherapy after multiple recurrences had an intermediate outcome. Multivariate analysis showed that refractory disease and systemic symptoms at the time of initial presentation were associated significantly associated with poor OS and EFS.CONCLUSIONSThe use of HDS chemotherapy for patients with refractory and/or recurrent HL is feasible at the multicenter level. The combination of intensive debulking and HDT with PBPC autografting offers a good chance of prolonged disease free survival for patients with their first recurrence of HL. Cancer 2003;97:2748–59. © 2003 American Cancer Society.DOI 10.1002/cncr.11414

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Section: Discussionmentioning

confidence: 99%

High‐dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma

Tarella

Cuttica

Vitolo

et al. 2003

Cancer

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“…In 2008, an entirely human granzyme B-based CFP directed against CD64 was found to be toxic for an acute myeloid leukemia (AML)-related cell line and primary AML cells with IC 50 values ranging between 1.7 and 17 nmol/L (27). The human RNase angiogenin was shown to be specifically cytotoxic toward CD30-overexpressing Hodgkin lymphoma-derived cell lines, when fused to the CD30 ligand (26). Another CD30-targeted CFP was shown to kill CD30-overexpressing tumor cells efficiently when combined with human death-associated protein kinase 2 (28).…”

Section: Discussionmentioning

confidence: 99%

“…Several human enzymes, including the protease granzyme B, RNase angiogenin, or death-associated protein kinase 2, have been demonstrated to induce apoptosis in target cells, when delivered by antigen-specific ligands or antibody fragments (26)(27)(28)(29). Similarly, death ligands of the tumor necrosis factor (TNF) family have been genetically fused to anticancer scFvs to selectively induce apoptosis in various forms of cancer (30,31).…”

Section: Introductionmentioning

confidence: 99%

EpCAM-Selective Elimination of Carcinoma Cells by a Novel MAP-Based Cytolytic Fusion Protein

Hristodorov

Amoury

Mladenov

et al. 2014

Molecular Cancer Therapeutics

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In normal epithelia, the epithelial cell adhesion molecule (EpCAM) expression is relatively low and only present at the basolateral cell surface. In contrast, EpCAM is aberrantly overexpressed in various human carcinomas. Therefore, EpCAM is considered to be a highly promising target for antibody-based cancer immunotherapy. Here, we present a new and fully human cytolytic fusion protein (CFP), designated "antiEpCAM(scFv)-MAP," that is comprised of an EpCAM-specific antibody fragment (scFv) genetically fused to the microtubule-associated protein tau (MAP). Anti-EpCAM(scFv)-MAP shows potent EpCAM-restricted proapoptotic activity toward rapidly proliferating carcinoma cells. In vitro assays confirmed that treatment with anti-EpCAM(scFv)-MAP resulted in the colocalization and stabilization of microtubules, suggesting that this could be the potential mode of action. Dose-finding experiments indicated that anti-EpCAM(scFv)-MAP is well tolerated in mice. Using noninvasive far-red in vivo imaging in a tumor xenograft mouse model, we further demonstrated that anti-EpCAM(scFv)-MAP inhibited tumor growth in vivo. In conclusion, our data suggest that anti-EpCAM(scFv)-MAP may be of therapeutic value for the targeted elimination of EpCAM þ carcinomas. Mol Cancer Ther; 13(9); 2194-202. Ó2014 AACR.

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“…In addition to human granzyme B, human RNases, such as angiogenin, have been used to replace nonhuman toxins (Hetzel et al, 2008;Stahnke et al, 2008;Mathew & Verma, 2009;Schiffer et al, 2013). The specific cytotoxicity of human angiogenin towards CD30-overexpressing HL-derived cell lines has been demonstrated by fusion with the CD30 ligand (Huhn et al, 2001). Another CD30-targeted CFP was shown to kill CD30-overexpressing tumour cells efficiently when combined with human deathassociated protein kinase 2 (DAPK; Tur et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, our group also reported on an improved version of granzyme B, which shows resistance against the endogenous inhibitor serpin B9 and thus overcomes one potential escape strategy of CD30 + lymphoma cells (Schiffer et al, 2013). In addition to granzyme B, the human RNase angiogenin was shown to be specifically cytotoxic towards CD30-overexpressing HL-derived cell lines, when fused to the CD30 ligand (Huhn et al, 2001). Another CD30-targeted CFP was shown to kill CD30-overexpressing tumour cells efficiently when combined with human death-associated protein kinase 2 (DAPK2; Tur et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Human microtubule‐associated protein tau mediates targeted killing of CD30⁺ lymphoma cells in vitro and inhibits tumour growth in vivo

et al. 2013

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SummaryHodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) are rare lymphoproliferative cancer types. Although most HL patients can be cured by chemo-and radio-therapy, 4-50% of patients relapse and have a poor prognosis. The need for improved therapeutic options for patients with relapsed or refractory disease has been addressed by CD30-specific antibody-based immunotherapeutics. However, available CD30-specific monoclonal antibodies (mAbs), antibody drug conjugates (ADCs) or chimeric immunotoxins suffer from the requirement of a functional host immunity, undesirable immune reactions or heterogeneity and instability, respectively. Here, we present a new fusion protein comprised of the CD30-specific antibody single-chain fragment Ki4(scFv) and the human pro-apoptotic effector protein, microtubule-associated protein tau (MAPT). Ki4(scFv)-MAP selectively induced apoptosis in rapidly proliferating L540cy, L428, and Karpas 299 cells in a dose-dependent manner. Tubulin polymerization assays confirmed that Ki4(scFv)-MAP stabilizes microtubules, suggesting a mechanism for its pro-apoptotic action. Dosefinding experiments proved that Ki4(scFv)-MAP is well tolerated in mice compared to the previously reported Ki4(scFv)-ETA'. Ki4(scFv)-MAP significantly inhibited growth of subcutaneous L540cy xenograft tumours in mice. Our data present a novel approach for the treatment of CD30 + lymphomas, combining the binding specificity of a target-specific antibody fragment with the selective cytotoxicity of MAPT towards proliferating lymphoma cells.

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Human angiogenin fused to human CD30 ligand (Ang-CD30L) exhibits specific cytotoxicity against CD30-positive lymphoma

Cited by 43 publications

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High‐dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma

High‐dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma

EpCAM-Selective Elimination of Carcinoma Cells by a Novel MAP-Based Cytolytic Fusion Protein

Human microtubule‐associated protein tau mediates targeted killing of CD30⁺ lymphoma cells in vitro and inhibits tumour growth in vivo

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Human angiogenin fused to human CD30 ligand (Ang-CD30L) exhibits specific cytotoxicity against CD30-positive lymphoma

Cited by 43 publications

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High‐dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma

High‐dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma

EpCAM-Selective Elimination of Carcinoma Cells by a Novel MAP-Based Cytolytic Fusion Protein

Human microtubule‐associated protein tau mediates targeted killing of CD30+ lymphoma cells in vitro and inhibits tumour growth in vivo

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Human microtubule‐associated protein tau mediates targeted killing of CD30⁺ lymphoma cells in vitro and inhibits tumour growth in vivo