Anti‐CD30‐IL‐12 antibody‐cytokine fusion protein that induces IFN‐γ secretion of T cells and NK cell‐mediated lysis of Hodgkin's lymphoma‐derived tumor cells

Heuser, Claudia; Diehl, Volker; Abken, Hinrich; Hombach, Andreas

doi:10.1002/ijc.11279

Cited by 22 publications

(24 citation statements)

References 36 publications

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“…Possibly, the addition of nonmyelosuppressive therapeutic agents such as humanized anti-CD30 monoclonal antibody or anti-CD30 immunoconjugates during the early post-transplant period may help to delay disease progression until the CC treatments can be safely started or may bypass certain chemotherapy resistance mechanisms altogether. [34][35][36][37] Novel drugs such as thalidomide or bortezimib may also be worth testing in the post-transplant setting. In addition, nonmyeloablative allogeneic transplants may induce cures even among patients with highly refractory disease through a graft-versus-host disease effect and could be applied to selected patients shortly after cytoreduction with autotransplantation.…”

Section: Discussionmentioning

confidence: 99%

Autologous stem cell transplantation followed by consolidation chemotherapy for relapsed or refractory Hodgkin's lymphoma

Rapoport

Guo

Badros

et al. 2004

Bone Marrow Transplant

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Summary:Relapse remains a major cause of treatment failure after autotransplantation (auto-PBSCT) for Hodgkin's disease (HD). The administration of non-crossresistant therapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after auto-PBSCT in 37 patients with relapsed or refractory HD. Patients received high-dose gemcitabine-BCNU-melphalan and auto-PBSCT followed by involved-field radiation and up to four cycles of the DCEP-G regimen, which consisted of dexamethasone, cyclophosphamide, etoposide, cisplatin, gemcitabine given at 3 and 9 months post transplant alternating with a second regimen (DPP) of dexamethasone, cisplatin, paclitaxel at 6 and 12 months post transplant. The probabilities of event-free survival (EFS) and overall survival (OS) at 2.5 years were 59% (95% CI ¼ 42-76%) and 86% (95% CI ¼ 71-99%), respectively. In all, 17 patients received 54 courses of CC and 15 were surviving event free (2.5 years, EFS ¼ 87%). There were no treatment-related deaths during or after the CC phase. Post-transplant CC is feasible and well tolerated. The impact of this approach on EFS should be evaluated in a larger, randomized study. PBSCT; auto-PBSCT; high-dose therapy; consolidation chemotherapy; gemcitabine High-dose therapy followed by autologous stem cell rescue has improved the long-term event-free (EFS) and overall survival (OS) for patients with relapsed or refractory Hodgkin's disease (HD). The probability of 5-year progression-free survival (PFS) for patients with HD autografted in first relapse ranged from 37 to 63% in selected series, while the PFS for patients autografted for primary refractory disease ranged from 15 to 50%. From these studies, predictors of better outcome after autotransplantation varied, but included 'minimal' disease status, chemosensitivity, normal LDH levels, good performance status, transplant in first relapse, absence of B symptoms at diagnosis, and administration of involvedfield radiotherapy post transplantation. In addition, factors identified by the International Prognostic Factors Project on advanced HD including low serum albumin, anemia, advanced age, and lymphocytopenia were associated with inferior EFS and OS rates after autotransplantation as well. 23 The chief cause of treatment failure after autotransplantation is relapse or progression of disease, which occurs in about 50% of transplanted patients. The majority of relapses occur in sites of prior disease but new and unusual sites of recurrence have been described including the leptomeninges. 11 To prevent or delay disease relapse after auto-PBSCT, a clinical protocol was developed that contained the following novel features: (1) the standard BEAM (BCNU-etoposide-cytarabine-melphalan) conditioning regimen was modified to include gemcitabine because of its single-agent activity in relapsed/refractory HD; 24 (2) dose-intensive cyclophosphamide and etoposide were used for pre-transplant cytoreduction and stem cell mobilization; (3) involv...

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Section: Discussionmentioning

confidence: 99%

Autologous stem cell transplantation followed by consolidation chemotherapy for relapsed or refractory Hodgkin's lymphoma

Rapoport

Guo

Badros

et al. 2004

Bone Marrow Transplant

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“…CD30 antigen expression in lymphoma has led to the development of an anti-CD30 antibody-(IL-12) fusion protein to enhance the antitumor response against human Hodgkin's lymphoma cells [130]. The anti-CD30 HRS3scFv, previously used to develop an antibody-(IL-2) fusion protein [82], was also used to develop HRS3scFv-hi-(IL-12) ( Figure 2A (IV)).…”

Section: Antibody-(il-12) Fusion Proteinsmentioning

confidence: 99%

“…This antibody-(IL-12) fusion protein binds to CD30 + L540 tumor cells (human Hodgkin's lymphoma) and retains its ability to induce IFN-γ secretion by activated T cells and resting NK cells. In addition, HRS3scFv-hi-(IL-12) promoted L1236 lymphoma cell lysis by NK cells in vitro [130].…”

Section: Antibody-(il-12) Fusion Proteinsmentioning

confidence: 99%

“…anti-HER2/neu (IL-12)-IgG3 HER2/neu Mammary and colon cancer Animal models [70,119,123,124,155,167] (IL-12)-L19 ED-B Colon cancer and teratocarcinoma Animal models [125][126][127] p40-scFvL19/scFvL19-p35 ED-B Teratocarcinoma Animal models [127] HRS3-scFv-hi-(IL-12) CD30 Hodgkin's lymphoma In vitro [130] HRS3-scFv-Fc-(IL-12) CD30 Hodgkin's lymphoma In vitro [170] aCEA-(IL-12) CEA Bile duct carcinoma In vitro [131] huBC1-(IL-12) Fibronectin Prostate, colon and skin cancer Animal models [129] * Tumor targeted by the antibody-cytokine fusion protein in animal models as described in the given references. Table 4 Bi-functional antibody-cytokine fusion proteins.…”

Section: Antibody Fusion Proteinmentioning

confidence: 99%

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Antibody–cytokine fusion proteins: applications in cancer therapy

Ortíz‐Sánchez

Helguera

Daniels

et al. 2008

Expert Opinion on Biological Therapy

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Background-Antibody-cytokine fusion proteins consist of cytokines fused to an antibody to improve antibody-targeted cancer immunotherapy. These molecules have the capacity to enhance the tumoricidal activity of the antibodies and/or activate a secondary antitumor immune response.Objective-To review the strategies used to develop antibody-cytokine fusion proteins and their in vitro and in vivo properties, including preclinical and clinical studies focusing on IL-2, IL-12 and GM-CSF. Methods-Articles were found by searching databases such as PubMed and Clinical Trials of the US National Institutes of Health.Results/conclusion-Multiple antibody-cytokine fusion proteins have demonstrated significant antitumor activity as direct therapeutics or as adjuvants of cancer vaccines in preclinical studies, paving the way for their clinical evaluation.

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“…The final expression plasmids pRSV-HRS3-scFv-Fc-IL2 and pRSV-HRS3-scFv-Fc-IL12 were stably expressed in 293T cells. 17 The secreted fusion proteins were detected by ELISA as described below and purified from cell culture supernatants by affinity chromatography as described. 18 Binding of the fusion protein to CD30 was determined by ELISA utilizing CD30-Fc fusion protein that was coated (1 mg/ml) onto 96-well microtiter plates (Nunc, Wiesbaden, Germany).…”

Section: Cell Linesmentioning

confidence: 99%

Simultaneous targeting of IL2 and IL12 to Hodgkin's lymphoma cells enhances activation of resting NK cells and tumor cell lysis

Hombach

Heuser

Abken

2005

Intl Journal of Cancer

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Hodgkin's disease (HD) is characterized by the accumulation of functionally anergic T cells in the vicinity of the malignant Hodgkin/ Reed-Sternberg (H/RS) cells. To revert cellular anergy against H/RS cells, we generated an anti-CD30-antibody-interleukin-(IL)-2 and an anti-CD30-antibody-IL12 fusion protein that target IL2 and IL12, respectively, specifically to CD30 + H/RS cells. Both antibody-cytokine fusion proteins act cooperatively in the activation of resting NK cells, the induction of IFN-g secretion and enhanced target cell lysis. The cooperative activity of the targeted cytokines suggests that the application of both antibody-cytokine fusion proteins may be particularly suitable for the specific immunotherapy of Hodgkin's lymphoma. ' 2005 Wiley-Liss, Inc.

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Anti‐CD30‐IL‐12 antibody‐cytokine fusion protein that induces IFN‐γ secretion of T cells and NK cell‐mediated lysis of Hodgkin's lymphoma‐derived tumor cells

Abstract: Interleukin-12 (IL-12

Cited by 22 publications

References 36 publications

Autologous stem cell transplantation followed by consolidation chemotherapy for relapsed or refractory Hodgkin's lymphoma

Autologous stem cell transplantation followed by consolidation chemotherapy for relapsed or refractory Hodgkin's lymphoma

Antibody–cytokine fusion proteins: applications in cancer therapy

Simultaneous targeting of IL2 and IL12 to Hodgkin's lymphoma cells enhances activation of resting NK cells and tumor cell lysis

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