Immunotoxins constructed with chimeric, short-lived anti-CD22 monoclonal antibodies induce less vascular leak without loss of cytotoxicity

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13 Citations (Scopus)

Abstract

An immunotoxin (IT) constructed with RFB4, a murine anti-CD22 monoclonal antibody, and the "deglycosylated" A chain of ricin has shown activity at safe doses in patients with non-Hodgkin lymphoma and in children with acute lymphoblastic leukemia. The dose limiting toxicity is vascular leak syndrome (VLS), which appears to be due to a unique amino acid motif in the ricin toxin A (RTA) chain that damages vascular endothelial cells. We mutated recombinant (r) RTA to disable this site, but await testing of the IT prepared with this mutant RTA in humans. Another possible approach to reducing IT-induced VLS is to shorten the half-life of the IT in vivo. We previously constructed a mouse-human chimeric RFB4 by grafting the variable genes of RFB4 onto the human IgG1k constant regions. Here, we report the expansion of our panel of mutant chimeric RFB4s (mcRFB4s) that lack the ability to bind to the neonatal Fc receptor (FcRn). In comparison with cRFB4, which had a T 1/2 of 263 h, the mcRFB4s had T 1/2s ranging from 39-106 h. ITs were constructed with these mcRFB4s and rRTA. The mcRFB4-RTA ITs retained their cytotoxicity in vitro and had shorter half lives than the parental cRFB4-RTA IT. In addition, the mcRFB4 IT with the shortest T 1/2 induced less pulmonary vascular leak in mice, which we have postulated is a surrogate marker for VLS in humans.

Original languageEnglish (US)
Pages (from-to)57-68
Number of pages12
JournalmAbs
Volume4
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Ricin
Immunotoxins
Blood Vessels
Monoclonal Antibodies
Amino Acid Motifs
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Non-Hodgkin's Lymphoma
Half-Life
Endothelial Cells
Biomarkers
Lung
Genes

Keywords

  • Anti-CD22
  • Chimeric
  • Fc mutations
  • Immunotoxins
  • Monoclonal antibody
  • Ricin A chain

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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title = "Immunotoxins constructed with chimeric, short-lived anti-CD22 monoclonal antibodies induce less vascular leak without loss of cytotoxicity",
abstract = "An immunotoxin (IT) constructed with RFB4, a murine anti-CD22 monoclonal antibody, and the {"}deglycosylated{"} A chain of ricin has shown activity at safe doses in patients with non-Hodgkin lymphoma and in children with acute lymphoblastic leukemia. The dose limiting toxicity is vascular leak syndrome (VLS), which appears to be due to a unique amino acid motif in the ricin toxin A (RTA) chain that damages vascular endothelial cells. We mutated recombinant (r) RTA to disable this site, but await testing of the IT prepared with this mutant RTA in humans. Another possible approach to reducing IT-induced VLS is to shorten the half-life of the IT in vivo. We previously constructed a mouse-human chimeric RFB4 by grafting the variable genes of RFB4 onto the human IgG1k constant regions. Here, we report the expansion of our panel of mutant chimeric RFB4s (mcRFB4s) that lack the ability to bind to the neonatal Fc receptor (FcRn). In comparison with cRFB4, which had a T 1/2 of 263 h, the mcRFB4s had T 1/2s ranging from 39-106 h. ITs were constructed with these mcRFB4s and rRTA. The mcRFB4-RTA ITs retained their cytotoxicity in vitro and had shorter half lives than the parental cRFB4-RTA IT. In addition, the mcRFB4 IT with the shortest T 1/2 induced less pulmonary vascular leak in mice, which we have postulated is a surrogate marker for VLS in humans.",
keywords = "Anti-CD22, Chimeric, Fc mutations, Immunotoxins, Monoclonal antibody, Ricin A chain",
author = "Liu, {Xiao Yun} and Pop, {Laurentiu M.} and John Schindler and Vitetta, {Ellen S.}",
year = "2012",
month = "1",
doi = "10.4161/mabs.4.1.18348",
language = "English (US)",
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T1 - Immunotoxins constructed with chimeric, short-lived anti-CD22 monoclonal antibodies induce less vascular leak without loss of cytotoxicity

AU - Liu, Xiao Yun

AU - Pop, Laurentiu M.

AU - Schindler, John

AU - Vitetta, Ellen S.

PY - 2012/1

Y1 - 2012/1

N2 - An immunotoxin (IT) constructed with RFB4, a murine anti-CD22 monoclonal antibody, and the "deglycosylated" A chain of ricin has shown activity at safe doses in patients with non-Hodgkin lymphoma and in children with acute lymphoblastic leukemia. The dose limiting toxicity is vascular leak syndrome (VLS), which appears to be due to a unique amino acid motif in the ricin toxin A (RTA) chain that damages vascular endothelial cells. We mutated recombinant (r) RTA to disable this site, but await testing of the IT prepared with this mutant RTA in humans. Another possible approach to reducing IT-induced VLS is to shorten the half-life of the IT in vivo. We previously constructed a mouse-human chimeric RFB4 by grafting the variable genes of RFB4 onto the human IgG1k constant regions. Here, we report the expansion of our panel of mutant chimeric RFB4s (mcRFB4s) that lack the ability to bind to the neonatal Fc receptor (FcRn). In comparison with cRFB4, which had a T 1/2 of 263 h, the mcRFB4s had T 1/2s ranging from 39-106 h. ITs were constructed with these mcRFB4s and rRTA. The mcRFB4-RTA ITs retained their cytotoxicity in vitro and had shorter half lives than the parental cRFB4-RTA IT. In addition, the mcRFB4 IT with the shortest T 1/2 induced less pulmonary vascular leak in mice, which we have postulated is a surrogate marker for VLS in humans.

AB - An immunotoxin (IT) constructed with RFB4, a murine anti-CD22 monoclonal antibody, and the "deglycosylated" A chain of ricin has shown activity at safe doses in patients with non-Hodgkin lymphoma and in children with acute lymphoblastic leukemia. The dose limiting toxicity is vascular leak syndrome (VLS), which appears to be due to a unique amino acid motif in the ricin toxin A (RTA) chain that damages vascular endothelial cells. We mutated recombinant (r) RTA to disable this site, but await testing of the IT prepared with this mutant RTA in humans. Another possible approach to reducing IT-induced VLS is to shorten the half-life of the IT in vivo. We previously constructed a mouse-human chimeric RFB4 by grafting the variable genes of RFB4 onto the human IgG1k constant regions. Here, we report the expansion of our panel of mutant chimeric RFB4s (mcRFB4s) that lack the ability to bind to the neonatal Fc receptor (FcRn). In comparison with cRFB4, which had a T 1/2 of 263 h, the mcRFB4s had T 1/2s ranging from 39-106 h. ITs were constructed with these mcRFB4s and rRTA. The mcRFB4-RTA ITs retained their cytotoxicity in vitro and had shorter half lives than the parental cRFB4-RTA IT. In addition, the mcRFB4 IT with the shortest T 1/2 induced less pulmonary vascular leak in mice, which we have postulated is a surrogate marker for VLS in humans.

KW - Anti-CD22

KW - Chimeric

KW - Fc mutations

KW - Immunotoxins

KW - Monoclonal antibody

KW - Ricin A chain

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