This is a fun one for me. Here's some precursor work............
Proc Natl Acad Sci U S A 1994 Aug 2;91(16):7727-31
A mutant epidermal growth factor receptor common in human glioma
confers enhanced tumorigenicity.
Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, Huang HJ.
Ludwig Institute for Cancer Research, La Jolla, CA 92093-0660.
The development and neoplastic progression of human astrocytic tumors appears to result
through an accumulation of genetic alterations occurring in a relatively defined order. One such
alteration is amplification of the epidermal growth factor receptor (EGFR) gene. This episomal
amplification occurs in 40-50% of glioblastomas, which also normally express endogenous
receptors. Moreover, a significant fraction of amplified genes are rearranged to specifically
eliminate a DNA fragment containing exons 2-7 of the gene, resulting in an in-frame deletion of
801 bp of the coding sequence of the extracellular domain. Here we used retroviral transfer of
such a mutant receptor (de 2-7 EGFR) into glioblastoma cells expressing normal endogenous
receptors to test whether the mutant receptor was able to augment their growth and malignancy.
Western blotting analysis showed that these cells expressed endogenous EGFR of 170 kDa as
well as the exogenous de 2-7 EGFR of 140-155 kDa. Although holo-EGFRs were
phosphorylated on tyrosine residues only after exposure of the cells to ligand, de 2-7 EGFRs
were constitutively phosphorylated. In tissue culture neither addition of EGF nor expression of the
mutant EGFR affected the rate of cell growth. However, when cells expressing mutant EGFR
were implanted into nude mice subcutaneously or intracerebrally, tumorigenic capacity was
greatly enhanced. These results suggest that a tumor-specific alteration of the EGFR plays a
significant role in tumor progression perhaps by influencing interactions of tumor cells with their
microenvironment in ways not easily assayed in vitro.
>> Is there not a similar blood/brain barrier in mice? <<
Yes.
>> If there is, would not this systemic administration be a promising development for a Mab against gliomas? <<
I'll answer your question with a question........ how does this work?? (I don't know the answer)..........
Nat Med 2000 Aug;6(8):916-9
Peripherally administered antibodies against amyloid beta-peptide enter
the central nervous system and reduce pathology in a mouse model of
Alzheimer disease.
Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang
J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen
M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T.
Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA.
fbard@elanpharma.com
One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and
its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene
driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress
one of the disease-linked mutant forms of the human amyloid precursor protein, show many of
the pathological features of Alzheimer disease, including extensive deposition of extracellular
amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with
human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several
hypotheses have been proposed regarding the mechanism of this response. Here we report that
peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce
amyloid burden. Despite their relatively modest serum levels, the passively administered
antibodies were able to enter the central nervous system, decorate plaques and induce clearance
of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer
disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear
plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These
results indicate that antibodies can cross the blood-brain barrier to act directly in the central
nervous system and should be considered as a therapeutic approach for the treatment of
Alzheimer disease and other neurological disorders. |
