INHIBITION OF TUMOR CELL GROWTH BY IMMUNOTOXINS

Project: Research project

Description

Tumor selective monoclonal antibodies chemically linked to toxin
polypeptides (IMT) inhibit the growth of respective cancer cells.
While these conjugates are very efficient in eliminating target
tumor cells in vitro, their application in vivo is limited due to i)
variable cytotoxicity, ii) escape of a minor population of cells
from IMT treatment, iii) instability of the conjugate in circulation
and iv) reduced tumor localization. The last two issues are
critical for the systemic application of IMT but could be
circumvent in treatment of tumors confined to restricted
anatomical space like the peritoneum (e.g. ovarian epithelial
carcinoma). Many IMTs have been prepared in the recent past
that are selective against breast and ovarian cancer cells. Some
of these conjugates made from recombinant ricin A-chain are
inactive inspite of efficient internalization. The chemical linkage
between antibody and the toxin moiety also plays a critical role in
determining the cytotoxicity. Therefore, in the proposed study,
attempts will be made to understand the reasons for reduced
immunotoxin activity and develop methods to overcome the lack
of efficacy. Earlier studies have shown that the presence of
lysosomotropic reagents increase the cytotoxicity of antibody-
toxin conjugates. However, this approach could not be used in
vivo due to faster clearance of the potentiating compound. Thus,
conjugation of lysosomotropic reagent like monensin to
macromolecules could increase its biological half-life and in turn
could improve the efficacy of IMT in vivo. Monensin would be
directed to tumor cells via a second antibody (carrier) recognizing
a distinct antigen. Alternatively, monensin would be encapsulated
in immunoliposomes for the specific delivery to tumor cells.
Improved tumor cell elimination could also be achieved by
targeting toxin molecules via dual epitopes present on the antigen
or via two distinct antigens present on the cancer cells. As toxin
polypeptides differ in their mode and site of action, it may be
possible to improve the IMT activity by linking two toxin moieties
to antibodies. These reagents will be tested for their ability to
enhance tumor cell elimination in vitro and in vivo in a nude
mouse xenograft tumor model system. Like in chemotherapy, a
small fraction of tumor cells do escape IMT treatment.
Investigations will be carried out to understand the mechanism of
resistance and based on the above work, methods to inhibit the
growth of these tumor cell variants will be studied.
StatusFinished
Effective start/end date7/1/886/30/96

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $148,534.00
  • National Institutes of Health

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Immunotoxins
Growth
Neoplasms
Melitten
Colicins
Ionophores
Neoplasm Antibodies
Monensin
Pancreatic Ribonuclease
Ovarian Neoplasms
Antibodies
Poisons
Protein Sorting Signals
Ion Channels
Monoclonal Antibodies
Point Mutation
Breast Neoplasms
Lysine
Bees
Cytoplasm