Tumoricidal effect of calicheamicin immuno-conjugates using a passive targeting strategy.
Calicheamicin is a potent chemotherapeutic with a low therapeutic index that requires targeting to tumor cells for its use in the clinic. To treat acute myeloid leukemia, calicheamicin has been conjugated to an antibody that recognizes CD33 (gemtuzumab ozogamicin). The application range of this 'active' targeting strategy is limited since it depends on specific antigen expression by tumor cells. This limitation could be reduced by using an antigen-independent 'passive targeting' strategy for calicheamicin. 'Passive targeting' relies on the dysfunctional vasculature of a neoplastic tumor that allows enhanced retention of macromolecules. We studied the efficacy of calicheamicin conjugated to various carrier molecules: i.e. immunoglobulin, albumin or PEGylated Fc fragments. In nude mice, a conjugate of anti-CD33 and calicheamicin accumulates in human tumor xenografts in the absence of detectable amounts of targeting antigen. Passive targeting provided sufficient accumulation of this conjugate to inhibit tumor growth of 10 different CD33-negative xenograft models. This efficacy depended on the use of an acid-labile linker between antibody and calicheamicin. Substitution of immunoglobulin as a carrier with either albumin or PEGylated Fc reduced or eliminated the efficacy of the conjugate. The results showed that using 'non-specific' immunoglobulin for passive targeting of calicheamicin might be an effective mode of cancer therapy.
Boghaert
Erwin R
ER
Wyeth Research, Pearl River, NY 10965, USA. boghaee@wyeth.com
Khandke
Kiran
K
Sridharan
Latha
L
Armellino
Douglas
D
Dougher
Maureen
M
Dijoseph
John F
JF
Kunz
Arthur
A
Hamann
Philip R
PR
Sridharan
Ashwin
A
Jones
Stanley
S
Discafani
Carolyn
C
Damle
Nitin K
NK
D000617:Aminoglycosides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D000079982:Gemtuzumab; D019073:HT29 Cells; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000737:chemistry; D000069283:Rituximab; D012709:Serum Albumin / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D012709:Serum Albumin; D011092:Polyethylene Glycols; D000069283:Rituximab; D000079982:Gemtuzumab