Anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-positive hematologic malignancies of childhood: preclinical studies and phase I clinical trial.
OBJECTIVE
Although most children with B-lineage acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma are cured, new agents are needed to overcome drug resistance and reduce toxicities of chemotherapy. We hypothesized that the novel anti-CD22 immunotoxin, RFB4(dsFv)-PE38 (BL22, CAT-3888), would be active and have limited nonspecific side effects in children with CD22-expressing hematologic malignancies. We conducted the first preclinical and phase I clinical studies of BL22 in that setting.


METHODS
Lymphoblasts from children with B-lineage ALL were assessed for CD22 expression by flow cytometry and for BL22 sensitivity by in vitro cytotoxicity assay. BL22 was evaluated in a human ALL murine xenograft model. A phase I clinical trial was conducted for pediatric subjects with CD22+ ALL and non-Hodgkin lymphoma.


RESULTS
All samples screened were CD22+. BL22 was cytotoxic to blasts in vitro (median IC(50), 9.8 ng/mL) and prolonged the leukemia-free survival of murine xenografts. Phase I trial cohorts were treated at escalating doses and schedules ranging from 10 to 40 microg/kg every other day for three or six doses repeated every 21 or 28 days. Treatment was associated with an acceptable safety profile, adverse events were rapidly reversible, and no maximum tolerated dose was defined. Pharmacokinetics were influenced by disease burden consistent with rapid drug binding by CD22+ blasts. Although no responses were observed, transient clinical activity was seen in most subjects.


CONCLUSIONS
CD22 represents an excellent target and anti-CD22 immunotoxins offer therapeutic promise in B-lineage hematologic malignancies of childhood.
Wayne
Alan S
AS
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1104, USA. waynea@mail.nih.gov
Kreitman
Robert J
RJ
Findley
Harry W
HW
Lew
Glen
G
Delbrook
Cynthia
C
Steinberg
Seth M
SM
Stetler-Stevenson
Maryalice
M
Fitzgerald
David J
DJ
Pastan
Ira
I
D000293:Adolescent; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004768:Enterotoxins / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007128:Immunoglobulin Fragments / Q000276:immunology; D000922:Immunotoxins / Q000627:therapeutic use*; D007223:Infant; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D020714:Maximum Tolerated Dose; D051379:Mice; D016513:Mice, SCID; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D014018:Tissue Distribution; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
D000906:Antibodies; C497867:CD22 protein, human; D004768:Enterotoxins; D007128:Immunoglobulin Fragments; D000922:Immunotoxins; C431326:RFB4(dsFv)-PE38 recombinant immunotoxin; D051918:Sialic Acid Binding Ig-like Lectin 2; C055966:immunoglobulin Fv