Systemic therapy with 3BIT, a triple combination cocktail of anti-CD19, -CD22, and -CD38-saporin immunotoxins, is curative of human B-cell lymphoma in severe combined immunodeficient mice.
We demonstrate in these preclinical studies that all severe combined immunodeficient mice injected with the human B-cell lymphoma cell line Ramos are cured when treated with a combination of anti-CD19, -CD22, and -CD38-saporin immunotoxins (ITs; termed 3BIT). Each component IT used individually did not cure the majority of animals but did significantly prolong their survival compared with PBS sham-treated controls, although the majority succumbed eventually to disease. The very significant improvement obtained with the three-IT combination 3BIT was not due to an antibody or antibody-plus-IT effect. We postulate that by targeting against these three cell surface molecules, we have effectively ensured delivery of saporin to each lymphoma cell with growth potential within the tumor, thus overcoming the problems of heterogeneity of target antigen expression that can limit the therapeutic efficacy of single-IT therapy or even two-IT combination therapy. These "proof of principle" findings have an obvious important bearing on antibody-based therapies for cancer and provide the rationale needed for the design and implementation of clinical trials with such combinations.
Flavell
D J
DJ
University Department of Pathology, Southampton General Hospital, Hampshire, United Kingdom.
Noss
A
A
Pulford
K A
KA
Ling
N
N
Flavell
S U
SU
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002051:Burkitt Lymphoma / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D015815:Cell Adhesion Molecules; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D000922:Immunotoxins / Q000627:therapeutic use*; D037102:Lectins; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D016513:Mice, SCID; D009699:N-Glycosyl Hydrolases; D009244:NAD+ Nucleosidase / Q000276:immunology; D010940:Plant Proteins / Q000627:therapeutic use*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D051918:Sialic Acid Binding Ig-like Lectin 2; D013047:Specific Pathogen-Free Organisms
D015703:Antigens, CD; D018941:Antigens, CD19; D000943:Antigens, Differentiation; D000944:Antigens, Differentiation, B-Lymphocyte; D000972:Antineoplastic Agents, Phytogenic; C497867:CD22 protein, human; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D000922:Immunotoxins; D037102:Lectins; D008562:Membrane Glycoproteins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D051918:Sialic Acid Binding Ig-like Lectin 2; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1