Complement-dependent and complement-independent cytotoxicity of polyclonal antithymocyte globulins in chronic lymphocytic leukemia

Ayuk, Francis; Atassi, Nabil; Schuch, Gunther; Mina, Sormeh; Bokemeyer, Carsten; Zander, Axel R.

doi:10.1016/j.leukres.2007.12.011

Cited by 18 publications

(14 citation statements)

References 34 publications

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“…A role for complement was suggested by results that showed enhanced cytotoxicity of thymoglobulin when cells were incubated in the presence of complement [36]. In our study, PAb also inhibited proliferation of MM in the presence of complement (Fig.…”

Section: Discussionsupporting

confidence: 65%

Polyclonal rabbit anti-murine plasmacytoma cell globulins induce myeloma cells apoptosis and inhibit tumour growth in mice

Yang

Gou

et al. 2011

Apoptosis

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Multiple myelomas (MMs) are etiologically heterogeneous and there are limited treatment options; indeed, current monoclonal antibody therapies have had limited success, so more effective antibodies are urgently needed. Polyclonal antibodies are a possible alternative because they target multiple antigens simultaneously. In this study, we produced polyclonal rabbit anti-murine plasmacytoma cell immunoglobulin (PAb) by immunizing rabbits with the murine plasmacytoma cell line MPC-11. The isolated PAb bound to plasma surface antigens in several MM cell lines, inhibited their proliferation as revealed by MTT assay, and induce apoptosis as indicated by flow cytometry, microscopic observation of apoptotic changes in morphology, and DNA fragmentation on agarose gels. The cytotoxicity of PAb on MPC-11 cell lines was both dose-dependent and time-dependent; PAb exerted a 50% inhibitory effect on MPC-11 cell viability at a concentration of 200 µg/ml in 48 h. Flow cytometry demonstrated that PAb treatment significantly increased the number of apoptotic cells (48.1%) compared with control IgG (8.3%). Apoptosis triggered by PAb was confirmed by activation of caspase-3, -8, and -9. Serial intravenous or intraperitoneal injections of PAb inhibited tumour growth and prolonged survival in mice bearing murine plasmacytoma, while TUNEL assay demonstrated that PAb induced statistically significant apoptosis (P < 0.05) compared to control treatments. We conclude that PAb is an effective agent for in vitro and in vivo induction of apoptosis in multiple myeloma and that exploratory clinical trials may be warranted.

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Section: Discussionsupporting

confidence: 65%

Polyclonal rabbit anti-murine plasmacytoma cell globulins induce myeloma cells apoptosis and inhibit tumour growth in mice

Yang

Gou

et al. 2011

Apoptosis

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“…Due to length of this chapter, we are unable to summarize all of the cutting‐edge issues that surround this research. For this reason, we refer to the recent literature on this subject 35–38 …”

Section: Resultsmentioning

confidence: 99%

Enhancing the Action of Rituximab in Chronic Lymphocytic Leukemia by Adding Fresh Frozen Plasma

Klepfish

Lugassy

Ioannis

et al. 2009

Annals of the New York Academy of Sciences

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Many patients with chronic lymphocytic leukemia (CLL) develop progressive treatment-resistant disease. Rituximab (RTX), a monoclonal antibody targeting CD20 on B lymphocytes and widely used in other indolent B-cell neoplasms is less efficacious in CLL, possibly because of associated complement deficiencies. Initial in vitro and in vivo observations support the central role of complement in rituximab-mediated loss of CD20(+) cells in CLL. In an open trial conducted in outpatient hematology clinics in Israel and Greece, we examined whether providing complement by concurrent administration of fresh frozen plasma (FFP) would enhance the effect of RTX in CLL. Five patients with severe treatment-resistant CLL were included in the trial. All had been previously treated with fludarabine, and three also failed treatment with RTX. Each patient was treated with two units of FFP followed with RTX 375 mg/m(2) as a single agent, repeated every 1-2 weeks as needed. A rapid and dramatic clinical and laboratory response was achieved in all patients. Lymphocyte counts dropped markedly followed by shrinkage of lymph nodes and spleen and improvement of the anemia and thrombocytopenia. This could be maintained over 8 months (median) with additional cycles if necessary. Treatment was well tolerated in all cases. In conclusion, adding FFP to RTX may provide a useful therapeutic option in patients with advanced CLL resistant to treatment. Further studies are needed to confirm and study the efficacy of the FFP/RTX combination in advanced CLL, establish the mechanisms, and possibly extend its use to other B-cell-dependent pathologies, such as treatment-refractory autoimmune diseases.

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“…At least 2 hypotheses exist: (1) ATG selectively interferes with GVHD but not graft-versusleukemia, and (2) ATG has a direct antileukemic effect, because it contains antibodies against antigens commonly expressed by both thymocytes/Jurkat cells and leukemic cells. We favor the latter hypothesis because, although there are no experimental data supporting the former hypothesis, ATG has been shown to induce apoptosis and complement lysis of leukemic cell lines and primary leukemic cells (acute leukemia blasts, chronic lymphocytic leukemia cells) in vitro [36][37][38][39][40].…”

Section: Relapse and Atg In Conditioning For Adult Bmt/pbsctmentioning

confidence: 99%

Rabbit Anti–T Cell Globulin in Allogeneic Hematopoietic Cell Transplantation

Storek

Mohty²,

Boelens

2015

Biology of Blood and Marrow Transplantation

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Anti-T cell globulin (ATG) is polyclonal IgG from rabbits immunized with human thymocytes or a human T cell line. Prophylaxis using ATG infused with conditioning for adult marrow or blood stem cell transplantation reduces both acute and chronic graft-versus-host disease (GVHD). However, ATG is not or minimally efficacious in steroid refractory GVHD treatment. Regarding preemptive therapy, ATG is promising; however, further work is needed on establishing adequate biomarkers to be used as triggers for preemptive therapy before it can be used routinely. Relapse is not increased by ATG, except possibly in the setting of reduced-intensity conditioning. Infections are probably increased when using high but not low-dose ATG, except for Epstein-Barr virus-driven post-transplantation lymphoproliferative disorder, which may be increased even with low-dose ATG. Survival is not improved with ATG; however, survival free of immunosuppressive therapy is improved. Pharmacokinetics of ATG are highly variable, resulting in highly variable areas under the time-concentration curves. Optimized dosing of ATG might improve transplantation outcomes. In conclusion, ATG reduces GVHD and, thus, may improve quality of life, without compromising survival.

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Complement-dependent and complement-independent cytotoxicity of polyclonal antithymocyte globulins in chronic lymphocytic leukemia

Cited by 18 publications

References 34 publications

Polyclonal rabbit anti-murine plasmacytoma cell globulins induce myeloma cells apoptosis and inhibit tumour growth in mice

Polyclonal rabbit anti-murine plasmacytoma cell globulins induce myeloma cells apoptosis and inhibit tumour growth in mice

Enhancing the Action of Rituximab in Chronic Lymphocytic Leukemia by Adding Fresh Frozen Plasma

Rabbit Anti–T Cell Globulin in Allogeneic Hematopoietic Cell Transplantation

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