Selection of antibodylead candidate for a stromal target and evaluation of efficacy in xenograft model
. The purpose of the experiment/project:
The purpose of this experiment is to select an antibody clone for TTC lead candidate for further development and evaluate it's pharmacokinetic properties and efficacy in xenograft cancer model. Previously, in experiment 14514 we have tested some clones with high affinity in the in vitro tests, however other factors we of importance for in vivo uptake. New clones for in vivo testing were modified to meet new criteria and will, in addition, provide required intellectual property rights.
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:
A selected target is differentially expressed in stromal tissue of epithelial cancers. Targeting it allows delivery of Th227, an alpha emitting isotope. This allows killing of resistant cancer cells, especially in triple negative breast cancer where choices of targets are limited.
IV. The number of animals and species:
Female tumor-bearing NMRI athymic nude mice will be used in the study. First, we will evaluate pharmacokinetic properties of isotype control and five targeting clones, requiring 84 tumor bearing mice. After a lead candidate will be selected, an in vivo efficacy in xenograft cancer model will be performed requiring 136 mice. If successful, 1 additional model will be evaluated, requiring 84+136=220 mice.
If not successful, new in vitro screening will be performed and new compounds will be produced in order to improve the performance of these targeting TTCs. New compounds will be tested in the same model as described above ,requiring 84+136=220 mice.
In total, PK and efficacy parts of the study, if fully completed, will require 220+220+220=660 mice. Accounting for take rate around 90% we would need 726 mice.
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies were conducted to prove the efficacy and specific killing of selected tumor models, as well as extensive characterization of the models was performed. We have earlier (ID 14514) performed an in vivo evaluation of several other drug candidates and identified factors required for uptake for this stromal target.
Selected xenograft cancer model was earlier used for in vivo efficacy study showing satisfactory tumor growth inhibition. We earlier established this model in a model development study with identification of expression level, optimal time point for treatment, study duration, potential adverse conditions, take rate and magnitude of effect. We reduce the number of animals used in the study by initiating the next phase only if the previous is successful. Technicians conduction the study have long experience with similar studies using well refined techniques.
The purpose of this experiment is to select an antibody clone for TTC lead candidate for further development and evaluate it's pharmacokinetic properties and efficacy in xenograft cancer model. Previously, in experiment 14514 we have tested some clones with high affinity in the in vitro tests, however other factors we of importance for in vivo uptake. New clones for in vivo testing were modified to meet new criteria and will, in addition, provide required intellectual property rights.
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:
A selected target is differentially expressed in stromal tissue of epithelial cancers. Targeting it allows delivery of Th227, an alpha emitting isotope. This allows killing of resistant cancer cells, especially in triple negative breast cancer where choices of targets are limited.
IV. The number of animals and species:
Female tumor-bearing NMRI athymic nude mice will be used in the study. First, we will evaluate pharmacokinetic properties of isotype control and five targeting clones, requiring 84 tumor bearing mice. After a lead candidate will be selected, an in vivo efficacy in xenograft cancer model will be performed requiring 136 mice. If successful, 1 additional model will be evaluated, requiring 84+136=220 mice.
If not successful, new in vitro screening will be performed and new compounds will be produced in order to improve the performance of these targeting TTCs. New compounds will be tested in the same model as described above ,requiring 84+136=220 mice.
In total, PK and efficacy parts of the study, if fully completed, will require 220+220+220=660 mice. Accounting for take rate around 90% we would need 726 mice.
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies were conducted to prove the efficacy and specific killing of selected tumor models, as well as extensive characterization of the models was performed. We have earlier (ID 14514) performed an in vivo evaluation of several other drug candidates and identified factors required for uptake for this stromal target.
Selected xenograft cancer model was earlier used for in vivo efficacy study showing satisfactory tumor growth inhibition. We earlier established this model in a model development study with identification of expression level, optimal time point for treatment, study duration, potential adverse conditions, take rate and magnitude of effect. We reduce the number of animals used in the study by initiating the next phase only if the previous is successful. Technicians conduction the study have long experience with similar studies using well refined techniques.