Research Summary
Roland Walter
"Internalization of Anti-CD33 Antibodies
"
Human CD33 is expressed by early myeloid and leukemic progenitors, but not
by pluripotent hematopoietic stem cells, and has been successfully used for
targeted therapy with immunoconjugates (e.g. gemtuzumab ozogamicin, GO; humanized
anti-CD33 antibody conjugated with the potent anti-tumor antibiotic calicheamicin)
in acute myeloid leukemia (AML). The success of this therapeutic approach
requires internalization of the antibody-CD33 complex, but the underlying
mechanism has not been studied so far. We have found in preliminary studies
that the rate of internalization of the antibody is greatest in AML blast
cells from patients who responded favorably to treatment with GO, and that
rapid internalization of CD33 may be dependent upon tyrosine kinase activity.
We therefore propose to study the factors responsible for receptor-mediated
internalization of anti-CD33 antibodies in detail. Specifically, we plan
to investigate which tyrosine kinases and which motifs on the cytoplasmic
tail of CD33 are of importance for fast CD33 internalization. We will also
determine why the rapid CD33 internalization is apparently not functional
in some cell lines with slower internalization of CD33 and whether rapid
internalization can be restored in such cell lines and primary AML cells.
Elucidation of the mechanism(s) of CD33 internalization would substantially
expand the current understanding of CD33 biology and could theoretically
lead to novel approaches for enhanced clinical efficacy of immunoconjugate
therapy of AML.
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