Back to Search
Start Over
Immunotoxins constructed with chimeric, short-lived anti-CD22 monoclonal antibodies induce less vascular leak without loss of cytotoxicity.
- Source :
-
MAbs [MAbs] 2012 Jan-Feb; Vol. 4 (1), pp. 57-68. - Publication Year :
- 2012
-
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 T1/2 of 263 h, the mcRFB4s had T1/2s ranging from 39 to 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 T1/2 induced less pulmonary vascular leak in mice, which we have postulated is a surrogate marker for VLS in humans.
- Subjects :
- Amino Acid Motifs
Animals
Antibodies, Monoclonal genetics
Antibodies, Monoclonal pharmacology
Antibodies, Monoclonal toxicity
Cell Line, Tumor
Child
Endothelium, Vascular cytology
Female
Humans
Immunotoxins chemistry
Immunotoxins genetics
Immunotoxins toxicity
Lymphoma, Non-Hodgkin immunology
Mice
Mutation
Recombinant Proteins genetics
Recombinant Proteins toxicity
Ricin chemistry
Ricin genetics
Ricin toxicity
Antibodies, Monoclonal immunology
Endothelium, Vascular drug effects
Immunotoxins pharmacology
Recombinant Proteins pharmacology
Ricin pharmacology
Sialic Acid Binding Ig-like Lectin 2 immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1942-0870
- Volume :
- 4
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- MAbs
- Publication Type :
- Academic Journal
- Accession number :
- 22327430
- Full Text :
- https://doi.org/10.4161/mabs.4.1.18348