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is a fundamental component of the innate immunity, which has been known for
many years to be involved in the recognition and elimination of invading
pathogens. Complement system is a key player of humoral immunity and participates
in largely diverse processes, such as clearance of immune complexes,
mobilization of hematopoietic stem-progenitor cells, control of adaptive
immunity and angiogenesis. The complement regulatory proteins (CRPs) optimize
the effect of complement and avoid excessive cell lysis. However, in cancer
patients, membrane complement regulatory proteins (mCRPs) have been reported to
be highly expressed in some cancer types on the surface of neoplastic cells. Hence,
they act as a major barrier for complement dependent cytotoxicity mediated by
therapeutic anticancer monoclonal antibodies especially in leukemia. The aim of
the current study is investigate the effect of CD46; a membrane complement
regulatory protein on tumor pathogenesis in Egyptian leukemia patients. The
study will be assessing the level of expression of CD46 in blood samples of
leukemia patients compared to healthy controls. Antisense short interfering RNA
(siRNA) will be applied to knock down the expression of CD46 with the aim of exploiting
such approach for reducing complement resistance of neoplastic cells on Raji
and REH tumor cell. Due to the clinical applicability of siRNA, the anti-sense
approach that will be used in this study may offer an additional alternative to
enhance the efficacy of antibody- and complement-based cancer immunotherapy.


cancer, leukemia, complements regulatory proteins, CD46, immunotherapy.


complement system is a central part of the innate immune response. It acts as        a first defense mechanism against invasive
microorganisms. It regulates the coagulation system and cell to cell
communications. It is also involved in angiogenesis and regeneration of tissues.
The complement system coordinates between the innate and adaptive immunity. It
increases the ability of phagocytic cells and antibodies to clear microbes and
damaged cells from an organism, promotes inflammation, and attacks the plasma
membrane of the pathogen 1,2. For decades, complement has been
recognized as an effector arm of the immune system that contributes to the
destruction of tumor cells. In fact, many therapeutic strategies have been
proposed that are based on the intensification of complement-mediated responses
against tumors. Despite substantial advances in the chemotherapeutic management
of cancer, more than half of all cancer patients do not respond to therapy or
relapse, dying from metastatic disease. Alternatively, cancer therapies
directed at immune modulation have also been pursued, but with only modest
advances to date.

of the complement activation is very crucial to keep the homeostasis of an
organism. Complement regulators are divided into two groups; soluble and
membrane-bound proteins. These complement regulatory proteins (CRPs) control
inappropriate complement attack if produced in normal amounts. Membrane
cofactor protein (CD46), decay-accelerating factor (CD55), and CD59 (protectin)
are examples of membrane-bound complement regulatory proteins (mCRPs) 3.
They control the complement activation at the level of C3. CD46 controls
cleavage of C3b and C4b, while CD55 causes C3/C5 convertases decay. CD59 works
on the terminal step of complement activation where it binds to C9 and hence,
prevents membrane attack complex (MAC) assembly. This inhibits the complement
dependent cytotoxicity (CDC) 4.  

studies have proven that membrane-bound complement regulatory proteins (mCRPs)
are overly expressed in neoplastic cells, which is a reason why the efficacy of
cancer-immunotherapy with complement-activating monoclonal antibodies is
limited 4,5. CD46 is an intrinsic complement inhibitor widely
distributed among leukocytes, endothelial cells, and epithelia but absent on
erythrocytes. Its structure consists of four short consensus repeats (SCR): a
serine/threonine-rich region (ST), a sequence of unknown significance (UK), a
transmembrane domain (TM) and a 16 or 23 amino acid cytoplasmic tail (CYT). It
irreversibly binds C3b and C4b where it acts as a cofactor for the plasma
serine protease factor I 5. According to previous studies, the
level of expression of mCRPs in neoplastic cells differs according to the type
of tumor, where in some tumors of the ductal carcinoma of the breast only one
of the three mCRPs was highly expressed, while in other tumors all three were
expressed. In colon carcinoma, all three were found to be highly expressed and
in non-small cell carcinoma of the lung, both CD46 and CD59 were highly
expressed whereas CD55 had a variable level of expression 6. Previous
studies used different approaches to neutralize the mCRPs as use of antibodies
that block their effect and using cytokines to downregulate mCRPs expression 4.
A better understanding of the molecular interactions between tumors and the
immune system should lead to better anticancer therapies.

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