Evaluation of pharmacokinetic properties, biodistribution and efficacy of modified Thorium-227-targeting conjugate
. The purpose of the experiment/project:
This study is a continuation study performed under FOTS 13101. In that study, we evaluated pharmacokinetic profile of Thorium-227 targeting conjugate with modified were modified. The study showed similar pharmacokinetic proterties for both test items. We also identified modifications that can increase binding affinitiy to the target.
The aim of this study is to evaluate the pharmacokinetic profile, biodistributuion and efficacy of modified Thorium-227 conjugates, a Thorium-227 labeled conjugate, speficially binding to a target commonly overexposed on the spesific cancer cells.
II. The expected adverse effects on the animals:
Three main adverse effects for the mice in this experiment are ulcerations of the tumors, weight reduction and reduction in white blood cell count. To eliminate the adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of ulcer or 15% weight reduction. White blood cell count didn't lead to any noticeable change in animal well-being. Else, animals will be immediately sacrificed with first signs of distress.
III. The expected scientific benefits or benefits for society:
The target is selectively expressed on the surface of cancer cells, where, generally, choices of targets and treatment regimes are limited. Both external radiation treatment, surgery and chemotherapy can significantly reduce quality of life for the patients. Thus, there is a need for more specific targeting of cancer cells and more mild treatment protocols. Spesific targeting allows delivery of Thorium-227, an alpha emitting isotope. This allows targeted killing of cancer cells. Compared to existing molecules, sugested new molecules can allow more beneficial biodistribution profile with less adverse effect.
IV. The number of animals and species:
In this study we aim to utilize a spesific cancer model, that is a known model with proved efficacy of Thorium-227 labeled antibody-chelator conjugates. Both the PK/biodistribution and efficacy studies of the modified test items will have to be performed. We will use 377 athymic nude mice in this study.
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies were conducted to prove the efficacy, characterization and specific killing in the cancer cells. We have already acquired promising data with other similar test items in the this model (ID:13101 and 8438), thus we have good knowledge of this model with regards to group size, timing of treatment etc. This experience has also lead to a reduction in the number of time points in the pharmacokinetic study, reducing the number of animals from 24 to 15 in each group. The technicians conducting the study have long experience with similar studies using well refined techniques.
This study is a continuation study performed under FOTS 13101. In that study, we evaluated pharmacokinetic profile of Thorium-227 targeting conjugate with modified were modified. The study showed similar pharmacokinetic proterties for both test items. We also identified modifications that can increase binding affinitiy to the target.
The aim of this study is to evaluate the pharmacokinetic profile, biodistributuion and efficacy of modified Thorium-227 conjugates, a Thorium-227 labeled conjugate, speficially binding to a target commonly overexposed on the spesific cancer cells.
II. The expected adverse effects on the animals:
Three main adverse effects for the mice in this experiment are ulcerations of the tumors, weight reduction and reduction in white blood cell count. To eliminate the adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of ulcer or 15% weight reduction. White blood cell count didn't lead to any noticeable change in animal well-being. Else, animals will be immediately sacrificed with first signs of distress.
III. The expected scientific benefits or benefits for society:
The target is selectively expressed on the surface of cancer cells, where, generally, choices of targets and treatment regimes are limited. Both external radiation treatment, surgery and chemotherapy can significantly reduce quality of life for the patients. Thus, there is a need for more specific targeting of cancer cells and more mild treatment protocols. Spesific targeting allows delivery of Thorium-227, an alpha emitting isotope. This allows targeted killing of cancer cells. Compared to existing molecules, sugested new molecules can allow more beneficial biodistribution profile with less adverse effect.
IV. The number of animals and species:
In this study we aim to utilize a spesific cancer model, that is a known model with proved efficacy of Thorium-227 labeled antibody-chelator conjugates. Both the PK/biodistribution and efficacy studies of the modified test items will have to be performed. We will use 377 athymic nude mice in this study.
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies were conducted to prove the efficacy, characterization and specific killing in the cancer cells. We have already acquired promising data with other similar test items in the this model (ID:13101 and 8438), thus we have good knowledge of this model with regards to group size, timing of treatment etc. This experience has also lead to a reduction in the number of time points in the pharmacokinetic study, reducing the number of animals from 24 to 15 in each group. The technicians conducting the study have long experience with similar studies using well refined techniques.