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Tumour cell killing using chemically engineered antibody constructs specific for tumour cells and the complement
C L Harris1, K S Kan, G T Stevenson
1Department of Medical Biochemistry, University of Wales College of Medicine, Cardiff, UK.
Clinical and Experimental Immunology
|February 1, 1997
Summary
Chemically engineered antibodies can overcome limitations in immunotherapy. These constructs, combined with human complement and complement inhibitors, effectively target and lyse neoplastic B lymphoid cells while sparing healthy cells.
Area of Science:
- Immunology
- Biotechnology
- Oncology
Background:
- Monoclonal antibody (MoAb) immunotherapy faces challenges due to limited effector activation by mouse antibodies and host cell protective mechanisms against complement.
- Effective strategies are needed to enhance antibody-dependent cell-mediated cytotoxicity and complement-mediated lysis in cancer therapy.
Purpose of the Study:
- To develop and evaluate chemically engineered antibody constructs for targeted cancer cell killing using human complement.
- To investigate the efficacy of bispecific antibodies in neutralizing complement inhibitors (CD59 and CD55) on neoplastic B lymphoid cells.
- To assess the cell-specific targeting capabilities of engineered antibodies in the presence of bystander cells.
Main Methods:
- Utilized Fab'gamma Fc gamma2 chimaeric antibodies targeting CD37 to activate the classical complement pathway.
- Employed bispecific F(ab'gamma)2 antibody constructs targeting CD19 or CD38, combined with CD59-neutralizing moieties.
- Assessed cell lysis in vitro using Raji (neoplastic B lymphoid) and K562 (bystander) cell lines, with and without complement inhibitors (anti-CD59, anti-CD55).
Main Results:
- Neutralization of CD59 alone resulted in 15-25% Raji cell lysis.
- Combined neutralization of CD59 and CD55 led to efficient Raji cell killing (70% lysis).
- One bispecific antibody demonstrated specific delivery to Raji cells, avoiding bystander K562 cells, dependent on antibody affinity combinations.
- Targeted lysis of Raji cells (30-40%) was achieved in mixed cell populations without significant killing of K562 cells.
Conclusions:
- Engineered antibody constructs can enhance complement-mediated lysis of neoplastic B lymphoid cells.
- Combinations of bispecific antibodies targeting tumor antigens and complement inhibitors offer a promising strategy for cancer therapy.
- These constructs may be valuable for ex vivo purging of bone marrow or in vivo tumor cell targeting.