1,721,042 research outputs found
Complement as a biological tool to control tumor growth
Full text linkDeposits of complement components have been documented in several human tumors suggesting a potential involvement of the complement system in tumor immune surveillance. In vitro and in vivo studies have revealed a double role played by this system in tumor progression. Complement activation in the cancer microenvironment has been shown to promote cancer growth through the release of the chemotactic peptide C5a recruiting myeloid suppressor cells. There is also evidence that tumor progression can be controlled by complement activated on the surface of cancer cells through one of the three pathways of complement activation. The aim of this review is to discuss the protective role of complement in cancer with special focus on the beneficial effect of complement-fixing antibodies that are efficient activators of the classical pathway and contribute to inhibit tumor expansion as a result of MAC-mediated cancer cell killing and complement-mediated inflammatory process. Cancer cells are heterogeneous in their susceptibility to complement-induced killing that generally depends on stable and relatively high expression of the antigen and the ability of therapeutic antibodies to activate complement. A new generation of monoclonal antibodies are being developed with structural modification leading to hexamer formation and enhanced complement activation. An important progress in cancer immunotherapy has been made with the generation of bispecific antibodies targeting tumor antigens and able to neutralize complement regulators overexpressed on cancer cells. A great effort is being devoted to implementing combined therapy of traditional approaches based on surgery, chemotherapy and radiotherapy and complement-fixing therapeutic antibodies. An effective control of tumor growth by complement is likely to be obtained on residual cancer cells following conventional therapy to reduce the tumor mass, prevent recurrences and avoid disabilities
Phage Display Technology for Human Monoclonal AntibodiesHuman Monoclonal Antibodies
No full textDuring the last 15 years in vitro technologies opened powerful routes to combine the generation of large libraries together with fast selection procedures to identify lead candidates. One of the commonest methods is based on the use filamentous phages. Antibodies (Abs) can be displayed successfully on the surface of phage by fusing the coding sequence of the antibody variable (V) regions to the phage minor coat protein pIII. By creating large libraries, antibodies with affinities comparable to those obtained using traditional hybridomas technology can be selected by a series of cycles of selection on antigen. As in this system antibody genes are cloned simultaneously with selection they can be easily further engineered for example by increasing their affinity (to levels unobtainable in the immune system), modulating their specificity or their effector function (by recloning into a full-length immunoglobulin scaffold). This chapter describes the basic protocols for antibody library construction, handling, and selection
In vivo targeting of human neutralizing antibodies against CD55 and CD59 to lymphoma cells increases the antitumor activity of rituximab.
No full textAn in vivo model of human CD20+ B-lymphoma was
established in severe combined immunodeficiency mice to
test the ability of human neutralizing miniantibodies to CD55
and CD59 (MB55 and MB59) to enhance the therapeutic effect
of rituximab. The miniantibodies contained single-chain
fragment variables and the hinge-CH2-CH3 domains of human
IgG1. LCL2 cells were selected for the in vivo study among
six B-lymphoma cell lines for their high susceptibility to
rituximab-dependent complement-mediated killing enhanced
by MB55 and MB59. The cells injected i.p. primarily colonized
the liver and spleen, leading to the death of the animals within
30 to 40 days. Thirty percent of mice receiving biotin-labeled
rituximab (25 Mg) i.p. on days 4 and 11 after cell injection
survived to 120 days. Administration of biotin-labeled
rituximab, followed by avidin (40 Mg) and biotin-labeled
MB55–MB59 (100 Mg) at 4-h intervals after each injection
resulted in the survival of 70% of mice. Surprisingly, 40%
of mice survived after the sole injection of avidin and biotin-
labeled MB55–MB59, an observation consistent with the
in vitro data showing that the miniantibodies induced killing
of f25% cells through antibody-dependent cell cytotoxicity.
In conclusion, MB55 and MB59 targeted to tumor cells
represent a valuable tool to enhance the therapeutic effect
of rituximab and other complement-fixing antitumor anti-
bodies
Humoral immunotherapy of multiple myeloma: perspectives and perplexities.
No full textIMPORTANCE OF THE FIELDS
Multiple myeloma (MM) is a hematological malignancy still remaining incurable despite the various therapies available, mainly because of the high fraction of refractory/relapsing cases. Therefore, the development of novel therapeutic approaches is urgently needed to overcome conventional treatment resistance.
AREAS COVERED IN THIS REVIEW:
In the era of targeted therapies, treatments combining a high specificity for neoplastic cells and the capability to interfere with environmental signals should be regarded as the weapons of choice. Monoclonal antibody (mAb)-based humoral immunotherapy could satisfy both these requirements when applied to MM. Indeed, many of the molecules expressed on MM cells, such as CD38, CD40, CD49d, CD138 and CD162 are involved in the adhesive dynamics regulating the crosstalk between MM and the BM-microenvironment.
WHAT THE READER WILL GAIN:
In this study we review those MM-associated molecules that have shown promising antitumor effects as targets of specific mAbs in preclinical settings, thus deserving to be considered for clinical investigation.
TAKE HOME MESSAGE:
mAbs directed against MM-associated adhesion markers should be taken into account in clinical practice, since they could possibly represent the best available combination of tumor cytotoxicity, environmental signal deprivation and immune system redirection
Selective therapeutic control of C5a and the terminal complement complex by anti-C5 single-chain Fv in an experimental model of antigen-induced arthritis in rats.
No full textTo determine the role of the terminal complement complex (TCC) in the development of experimental antigen-induced arthritis (AIA) and the therapeutic effects of human anti-C5 single-chain Fv (scFv).Two different anti-C5 scFv, one that inhibits both release of C5a and assembly of the TCC (TS-A 12/22) and another that selectively blocks formation of the TCC (TS-A 8), were injected at the onset of AIA. The effects of these scFv on disease severity were evaluated for up to 21 days and compared with the effects of injection of an unrelated scFv. AIA was also established in C6-deficient and C6-sufficient PVG rats to obtain further information on the role of the TCC in this model.TS-A 12/22 and TS-A 8 proved to be equally effective in reducing joint swelling, cell counts and tumor necrosis factor alpha levels in synovial lavage fluids, and the degree of histomorphologic changes compared with the effects of the unrelated scFv. TS-A 12/22 and TS-A 8 prevented the deposition of C9 but not that of C3, confirming the ability of the 2 scFv to neutralize C5. Administration of the 2 anti-C5 scFv after AIA onset also reduced disease severity. In C6-deficient rats with AIA, disease activity was reduced markedly compared with that in C6-sufficient rats.These 2 human anti-C5 scFv could represent potential therapeutic reagents to be used in patients with rheumatoid arthritis. In addition, the finding that TS-A 8 was as effective as TS-A 12/22 in reducing disease severity suggests that the TCC is mainly responsible for the joint inflammation and damage observed in AIA
Complement activated by chimeric anti-folate receptor antibodies is an efficient effector system to control ovarian carcinoma.
No full textIn vivo biodistribution and lifetime analysis of cy5.5-conjugated rituximab in mice bearing lymphoid tumor xenograft using time-domain near-infrared optical imaging.
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