FCRL1 on chronic lymphocytic leukemia, hairy cell leukemia, and B-cell non-Hodgkin lymphoma as a target of immunotoxins.
FCRL1 (Fc receptor-like 1) is a cell-surface membrane protein belonging to FCRL family and is preferentially expressed on B cells. To evaluate FcRL1 as an immunotherapy target for B-cell malignancies, we prepared anti-FCRL1 mAbs without cross-reactivity to other FCRL family proteins and analyzed FCRL1 protein expression on malignant cells from patients and on B-cell lines. Frequent FCRL1 expression was observed by flow cytometry on 12 B-cell non-Hodgkin lymphoma (B-NHL) cell lines and many patient samples: 12 of 14 chronic lymphocytic leukemia (CLL), 7 of 7 follicular lymphoma (FL), 13 of 17 hairy cell leukemia (HCL), and 2 of 3 mantle cell lymphoma (MCL). Two recombinant immunotoxins, E3(Fv)-PE38 and E9(Fv)-PE38, were constructed. Both immunotoxins bound to FCRL1-positive cells with similar affinities (3.4 and 3.2 nM) and were cytotoxic to cell lines, but E9(Fv)-PE38 was 4- to 20-fold more cytotoxic than E3(Fv)-PE38. The concentrations that inhibited response by 50% (IC(50)s) of E9(Fv)-PE38 on 11 different FCRL1-positive cell lines ranged from 1.0 ng/mL to 90 ng/mL and correlated with the FCRL1 expression levels. Our results suggest that anti-FCRL1 immunotoxin E9(Fv)-PE38 exhibits remarkably specific cytotoxicity and merits further evaluation for the treatment of FCRL1-positive malignancies, including CLL, HCL, FL, MCL, and other B-NHL.
Du
Xing
X
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
Nagata
Satoshi
S
Ise
Tomoko
T
Stetler-Stevenson
Maryalice
M
Pastan
Ira
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007167:Immunotherapy; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology; D066298:In Vitro Techniques; D007943:Leukemia, Hairy Cell / Q000276:immunology / Q000628:therapy*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000628:therapy*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011961:Receptors, Fc; D011971:Receptors, Immunologic / Q000276:immunology*
D000911:Antibodies, Monoclonal; C452186:FCRLA protein, human; D000922:Immunotoxins; D011961:Receptors, Fc; D011971:Receptors, Immunologic