As
therapeutics,
antibodies can be used "un-armed" or as
immunoconjugates to direct cytotoxic moieties to
tumor cells.
Immunoconjugates are made by attaching
chemotherapy drugs,
radioisotopes or toxins to the antibody. Small recombinant
antibody fragments fused to cytotoxic moieties, termed recombinant
immunotoxins are also being developed as an additional approach for a targeted
cancer therapy. Key parameters in determining the therapeutic potential of such targeted
therapies are target specificity, affinity, stability and size. With regard to treating solid
tumors,
tumor penetration (which is inversely proportional to size) is currently regarded as the prime factor for efficacy, while parameters such as binding affinity and residence time in the body are thought to contribute to a lesser extent. When comparing recombinant
immunotoxins and antibody-toxin
immunoconjugates that target ErbB2/HER2, here we found that a bivalent antibody-toxin
immunoconjugate (200 kDa) was superior to the corresponding recombinant monovalent
immunotoxin (69 kDa) in killing ErbB2-expressing
tumor cells in culture and as xenografts in nude mice, suggesting that higher avidity and longer residence time may outweigh
tumor penetration. Our study suggests that the re-valuation of currently neglected, large
IgG-effector molecule conjugates for anti-
cancer therapy may be justified.