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Comparative Study
. 2011 Apr;3(4):409-19.
doi: 10.3390/toxins3040409. Epub 2011 Apr 6.

A comparison of the anti-tumor effects of a chimeric versus murine anti-CD19 immunotoxins on human B cell lymphoma and Pre-B acute lymphoblastic leukemia cell lines

Lydia K Tsai  1 , Laurentiu M Pop, Xiaoyun Liu, Ellen S Vitetta
Affiliations
Comparative Study

A comparison of the anti-tumor effects of a chimeric versus murine anti-CD19 immunotoxins on human B cell lymphoma and Pre-B acute lymphoblastic leukemia cell lines

Lydia K Tsai et al. Toxins (Basel). 2011 Apr.

Abstract

Precursor B cell acute lymphoblastic leukemia (pre-B ALL) affects five to six thousand adults and almost three thousand children every year. Approximately 25% of the children and 60% of the adults die from their disease, highlighting the need for new therapies that complement rather than overlap chemotherapy and bone marrow transplantation. Immunotherapy is a class of therapies where toxicities and mechanisms of action do not overlap with those of chemotherapy. Because CD19 is a B cell- restricted membrane antigen that is expressed on the majority of pre-B tumor cells, a CD19-based immunotherapy is being developed for ALL. In this study, the anti-tumor activities of immunotoxins (ITs) constructed by conjugating a murine monoclonal antibody (MAb), HD37, or its chimeric (c) construct to recombinant ricin toxin A chain (rRTA) were compared both in vitro using human pre-B ALL and Burkitt's lymphoma cell lines and in vivo using a disseminated human pre-B ALL tumor cell xenograft model. The murine and chimeric HD37 IT constructs were equally cytotoxic to pre-B ALL and Burkitt's lymphoma cells in vitro and their use in vivo resulted in equivalent increases in survival of SCID mice with human pre-B ALL tumors when compared with control mice.

Keywords: chimerization; anti-CD19; ricin A chain.

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Figures

Figure 1
Figure 1
SDS-PAGE analysis of the purified cHD37 and HD37 MAbs. A 4–15% gradient gel was performed under non-reducing (lanes 2 and 3) and reducing (lanes 4 and 5) conditions. Lane 1: molecular weight markers; lanes 2 and 4: murine HD37; lanes 3 and 5: cHD37. This is one representative gel from three experiments.
Figure 2
Figure 2
SDS-PAGE analysis of the purified cHD37-rRTA and HD37-rRTA ITs.A 4–15% gradient gel was performed under non-reducing conditions. Lane 1, molecular weight markers; lane 2: cHD37-rRTA; lane 3: HD37-rRTA; lane 4: HD37-dgRTA. This is one representative gel from three experiments.
Figure 3
Figure 3
Binding of HD37 IT and MAb constructs to CD19+ cell lines. The ability of the ITs and MAbs to bind CD19+ (A) NALM-6, (B) Daudi, (C) Namalwa, and (D) Raji cells was assessed by flow cytometry. Diamonds: RFT5-dgRTA; open circles: MOPC-21(control); squares: cHD37; circles: HD37; triangles: HD37-rRTA; inverted triangles: cHD37-rRTA. Data represent means ± SD of three experiments.
Figure 4
Figure 4
Cytotoxicity of HD37 IT constructs on CD19+ cells lines.The cytotoxicity of the HD37 IT constructs were evaluated by [3H]thymidine incorporation on (A) NALM-6, (B) Daudi, (C) Namalwa, and (D) Raji cells. Triangles: RFT5-dgRTA; squares: cHD37-rRTA; circles: HD37-rRTA.
Figure 5
Figure 5
Therapeutic efficacy of the HD37 IT constructs in SCID mice with NALM-6 tumor cell xenografts. SCID/NALM-6 mice were treated on days 1 through 4 after tumor inoculation with the following ITs (5 mice per treatment group): open circles: PBS; open squares: RFT5-dgRTA; inverted triangles: HD37-rRTA; diamonds: cHD37-rRTA; circles: HD37-dgRTA. Arrows indicate treatment days (1–4). The graphs are representative of three separate experiments.
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