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Neutralization of membrane complement regulators improves complement-dependent effector functions of therapeutic
Srinivas Mamidi1, Simon Höne1, Claudia Teufel1
1Institute for Immunology; University of Heidelberg ; Heidelberg, Germany.
Oncoimmunology
|May 8, 2015
Summary
Therapeutic anticancer monoclonal antibodies (mAbs) efficacy is improved by inhibiting membrane complement regulatory proteins (mCRPs). Blocking mCRPs enhances complement-dependent cytotoxicity (CDC) and phagocytosis of leukemia cells, improving mAb effectiveness.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Therapeutic anticancer monoclonal antibodies (mAbs) utilize complement-dependent cytotoxicity (CDC) as a key effector mechanism.
- Malignant cells often resist CDC due to overexpression of membrane complement regulatory proteins (mCRPs) like CD46, CD55, and CD59.
- Differential sensitivity to CDC exists among leukemia cell types, impacting mAb efficacy.
Purpose of the Study:
- To investigate the role of mCRPs in mediating resistance to mAb-induced CDC in leukemia.
- To evaluate the impact of mCRPs inhibition on enhancing CDC and other effector functions of therapeutic mAbs.
- To determine if combined mAb therapy and mCRPs blockade can improve anti-leukemia immune responses.
Main Methods:
- Utilized various leukemia cell lines (Raji, REH) and primary chronic lymphocytic leukemia (CLL) cells.
- Administered therapeutic mAbs: rituximab (RTX), ofatumumab (OFA), and alemtuzumab (ALM).
- Employed mCRPs-specific siRNAs and neutralizing antibodies to inhibit mCRPs expression.
- Assessed complement-dependent cytotoxicity (CDC), C3 opsonization, and antibody-dependent cellular phagocytosis (ADCP) via flow cytometry and co-culture assays with peripheral blood lymphocytes (PBLs) and macrophages.
Main Results:
- Rituximab-resistant CD20-positive Burkitt lymphoma Raji cells and primary CLL cells showed enhanced CDC upon mCRPs inhibition.
- Ofatumumab demonstrated greater efficacy than rituximab in killing resistant cells, further augmented by mCRPs blockade.
- Alemtuzumab-induced CDC on primary CLL cells was enhanced by mCRPs inhibition.
- All tested mAbs induced C3 opsonization, significantly increased after mCRPs blockade, leading to enhanced cell-mediated cytotoxicity and macrophage phagocytosis of leukemia cells.
Conclusions:
- Inhibition of membrane complement regulatory proteins (mCRPs) effectively sensitizes leukemic cells to complement-dependent cytotoxicity (CDC).
- Combined blockade of mCRPs with therapeutic mAbs significantly enhances anti-leukemia immune responses, including phagocytosis.
- Targeting mCRPs represents a promising strategy to overcome resistance and improve the therapeutic efficacy of anticancer mAbs in leukemia treatment.
Keywords:
ADCC, antibody-dependent cellular cytotoxicityALM, AlemtuzumabCDC, complement-dependent cytotoxicityCDCC, complement-dependent cellular cytotoxicityMAC, membrane attack complexNHS, Normal Human SerumOFA, OfatumumabPBLs, peripheral blood leukocytesRTX, RituximabTRX, Trastuzumabalemtuzumabchronic lymphocytic leukemiacomplement regulatory proteinscomplement-dependent cytotoxicitymCRP, membrane-bound complement regulatory proteinofatumumabopsonizationrituximabsiRNA, small interfering RNAMore Related Videos
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