Cancer Treatment
Reviews
Two-phase monoclonal
(1990)
17, 355-356
radioimmunotherapy using bispectic antibodies (bs MAbs)
K. Bosslet, P. Hermentin, H. H. Sedlacek Research Laboratories
L. Kuhlmann,
of Behringwerke
A. Steinstraesser,
AC, 3550 Marburg,
G. Seemann
and
F.R.G.
lmmunoscintigraphy using Tc-99m labelled MAbs binding to selective epitopes on tumorassociated antigens (TAA) expressed on gastrointestinal tract carcinomas is going to become a routine diagnostic methodology in nuclear medicine. In contrast, radioimmunotherapy with isotope-tagged MAbs against solid tumors has so far been unsuccessful perhaps because of the unfavourable whole body distribution and tumor penetration of the radio-labelled MAbs which are macromolecules of about 150 kDA. Despite the potential of MAbs to selectively target tumors in viva the absolute amounts of radio-label that attaches to the tumor site is insufficient to induce any therapeutic effects. This is mainly due to the fact that the penetration and specific binding of MAbs to solid tumor masses in viva is a process which takes several days, whereas the unspecific uptake in the liver and other parenchymatous organs, followed by metabolization, is fast and quantitatively large. This leads to unfavourable dosimetry. In contrast, molecules oflow molecular weight (i.e. small hydrophilic hormones, MW < 5 kDa) penetrate tissues very fast and bind to their specific receptors rapidly. At the same time, their excretion via the kidneys is very efficient leading to a plasma half-life of only a few minutes. This pharmacodynamic behaviour leads to a rapid high signal-to-background ratio at the receptor site in the target tissue compared to receptor-negative tissues or the blood pool (1). Because most human tumors do not express selective receptors for small molecules which distribute extracellularly, this type of receptor targeting is restricted to the presence of a natural receptor and ligand system which can be labelled with an appropriate isotope. We tried to circumvent this problem by creating a new receptor on tumors selective for diethylenetriaminepentaacetic acid labelled with “‘Y (DTPA-“‘Y), a small hydrophilic complexon with a high complex constant for the b-emitter “Y. This new receptor was created using a quadroma-produced bs MAb having one arm selective for CEA and a second arm binding to EDTA-“‘Y. Injection of this bs MAb in repetitive high doses for 2 weeks in gastrointestinal tract carcinoma patients should result in binding to the tumorassociated CEA via the anti-CEA arm and creation of a new anti-DTPA-Y”Y receptor on the tumor cell membrane. According to our saturation experiments in nude mice, using anti-CEAand anti-GIT-mucin MAbs, these MAbs remain bound in human tumor xenografts for longer than 20 days. This favourable long-term storage after the assumed saturation of epitopes in the tumor site allows us to wait until the non-bound bs MAb is eliminated from large parenchymatous organs and the blood pool. Thereafter, when the 0305~ 7372/90/2&3355
+ 02 $03.00/0
0 355
1990 Academic
Press Limited
356
K. BOSSLET
ET AL
ratio between the tumor-associated new anti-DTPA-“‘Y receptor and the normal tissue background is optimal, a therapeutic dose of DTP,4-“Y will be injected intravenously. The non-receptor bound DTPA-“Y should be eliminated rapidly via the kidneys (halflife 30 min) whereas some DTPA-“Y should penetrate the tumor tissue and bind to the high-affinity, anti-DTPA-goY arm of the bs MAb present as a new receptor on the tumor. This should result in a significant irradiation of tumor cells and a minimal irradiation of normal tissues. The success of this two-phase radioimmunotherapy approach will mainly depend on the affinity of the anti-DTPA-goY arm of the bs MAb to DTPA-“Y. The amounts of accessible TAA epitopes and the storage of the bs MAb in the tumor are probably less critical. In summary, we would like to think that two-phase radioimmunotherapy consisting of a long-term, non-toxic localization and epitope saturation phase of a bs MAb followed by a short-term localization and toxic phase of DTPA-“Y might become a method which would allow the successful treatment of solid tumors without significant side-effects.
References 1. Thomas, G. D., Chappell, M. J., Dykes, P. W., Ramsden, D. B., Godfrey, A. R. (1989) Effect of dose, molecular size, affinity and protein binding ligand: A biomathematical model. Cancer RD. 49: 3290-3296.
K. R., Ellis, J, R. M., Bradwell, on turnour uptake of antibody or
Reviews
Two-phase monoclonal
(1990)
17, 355-356
radioimmunotherapy using bispectic antibodies (bs MAbs)
K. Bosslet, P. Hermentin, H. H. Sedlacek Research Laboratories
L. Kuhlmann,
of Behringwerke
A. Steinstraesser,
AC, 3550 Marburg,
G. Seemann
and
F.R.G.
lmmunoscintigraphy using Tc-99m labelled MAbs binding to selective epitopes on tumorassociated antigens (TAA) expressed on gastrointestinal tract carcinomas is going to become a routine diagnostic methodology in nuclear medicine. In contrast, radioimmunotherapy with isotope-tagged MAbs against solid tumors has so far been unsuccessful perhaps because of the unfavourable whole body distribution and tumor penetration of the radio-labelled MAbs which are macromolecules of about 150 kDA. Despite the potential of MAbs to selectively target tumors in viva the absolute amounts of radio-label that attaches to the tumor site is insufficient to induce any therapeutic effects. This is mainly due to the fact that the penetration and specific binding of MAbs to solid tumor masses in viva is a process which takes several days, whereas the unspecific uptake in the liver and other parenchymatous organs, followed by metabolization, is fast and quantitatively large. This leads to unfavourable dosimetry. In contrast, molecules oflow molecular weight (i.e. small hydrophilic hormones, MW < 5 kDa) penetrate tissues very fast and bind to their specific receptors rapidly. At the same time, their excretion via the kidneys is very efficient leading to a plasma half-life of only a few minutes. This pharmacodynamic behaviour leads to a rapid high signal-to-background ratio at the receptor site in the target tissue compared to receptor-negative tissues or the blood pool (1). Because most human tumors do not express selective receptors for small molecules which distribute extracellularly, this type of receptor targeting is restricted to the presence of a natural receptor and ligand system which can be labelled with an appropriate isotope. We tried to circumvent this problem by creating a new receptor on tumors selective for diethylenetriaminepentaacetic acid labelled with “‘Y (DTPA-“‘Y), a small hydrophilic complexon with a high complex constant for the b-emitter “Y. This new receptor was created using a quadroma-produced bs MAb having one arm selective for CEA and a second arm binding to EDTA-“‘Y. Injection of this bs MAb in repetitive high doses for 2 weeks in gastrointestinal tract carcinoma patients should result in binding to the tumorassociated CEA via the anti-CEA arm and creation of a new anti-DTPA-Y”Y receptor on the tumor cell membrane. According to our saturation experiments in nude mice, using anti-CEAand anti-GIT-mucin MAbs, these MAbs remain bound in human tumor xenografts for longer than 20 days. This favourable long-term storage after the assumed saturation of epitopes in the tumor site allows us to wait until the non-bound bs MAb is eliminated from large parenchymatous organs and the blood pool. Thereafter, when the 0305~ 7372/90/2&3355
+ 02 $03.00/0
0 355
1990 Academic
Press Limited
356
K. BOSSLET
ET AL
ratio between the tumor-associated new anti-DTPA-“‘Y receptor and the normal tissue background is optimal, a therapeutic dose of DTP,4-“Y will be injected intravenously. The non-receptor bound DTPA-“Y should be eliminated rapidly via the kidneys (halflife 30 min) whereas some DTPA-“Y should penetrate the tumor tissue and bind to the high-affinity, anti-DTPA-goY arm of the bs MAb present as a new receptor on the tumor. This should result in a significant irradiation of tumor cells and a minimal irradiation of normal tissues. The success of this two-phase radioimmunotherapy approach will mainly depend on the affinity of the anti-DTPA-goY arm of the bs MAb to DTPA-“Y. The amounts of accessible TAA epitopes and the storage of the bs MAb in the tumor are probably less critical. In summary, we would like to think that two-phase radioimmunotherapy consisting of a long-term, non-toxic localization and epitope saturation phase of a bs MAb followed by a short-term localization and toxic phase of DTPA-“Y might become a method which would allow the successful treatment of solid tumors without significant side-effects.
References 1. Thomas, G. D., Chappell, M. J., Dykes, P. W., Ramsden, D. B., Godfrey, A. R. (1989) Effect of dose, molecular size, affinity and protein binding ligand: A biomathematical model. Cancer RD. 49: 3290-3296.
K. R., Ellis, J, R. M., Bradwell, on turnour uptake of antibody or
