Defining Design Rules for Next-Generation Snakebite Antivenoms
Natalie Morris
University of Bristol, Bristol, UK
Wednesday, March 15th at 9:00 PDT
Register for free at https://rosaandco.com/webinars
Abstract
Snakebite is a neglected tropical disease which causes over 100,000 deaths and
400,000 cases of disability each year. Snakebite is treated using antivenoms,
which are currently produced by hyper-immunising horses against a venom and
harvesting their toxin-neutralising antibodies. There is an urgent need to
improve the way that we design and produce antivenoms, owing to limitations in
their cost, efficacy, and safety. In recent years, in vitro antibody selection
has made new antivenom scaffolds accessible for researchers. There is currently
no consensus as to the pharmacokinetic properties of an optimised antivenom,
and whether these change depending on the type of venom being treated. To
address this question computationally, we built a compartmental model of
snakebite envenomation and treatment. The model tracks the movement of venom,
antivenom, and neutralised venom through blood and tissue. The model was
parameterised with experimental data from rabbits. It enables user-control of
several treatment scenario parameters and antivenom design parameters
(antivenom size, dose, affinity, and valency).
We have applied our model to explore the impact of different antivenom design
features on treatment outcome. We simulated treatment of two model venoms with
a set of theoretical antivenoms, across a range of treatment time delays.
Global parameter optimisation and global sensitivity analysis show kon to
primarily mediate treatment efficacy. While molecular weight has a negligible
direct impact on treatment outcome, low molecular weight scaffolds can be more
easily designed for optimised treatment, particularly when treatment is
delayed. The same underlying trends are seen for both venom types tested. This
approach can be used to elucidate the dynamics of envenomation-treatment
systems, and inform the development of next-generation antivenoms.
March Modeling Webinar: Pharmacokinetic modeling for antivenom development
This is a great example for the use of PK/PD and should be of interest to
anyone developing venom-based drugs or antibody/nanobody drugs.
Defining Design Rules for Next-Generation Snakebite Antivenoms
Natalie Morris
University of Bristol, Bristol, UK
Wednesday, March 15th at 9:00 PDT
Register for free at https://rosaandco.com/webinars
Abstract
Snakebite is a neglected tropical disease which causes over 100,000 deaths and
400,000 cases of disability each year. Snakebite is treated using antivenoms,
which are currently produced by hyper-immunising horses against a venom and
harvesting their toxin-neutralising antibodies. There is an urgent need to
improve the way that we design and produce antivenoms, owing to limitations in
their cost, efficacy, and safety. In recent years, in vitro antibody selection
has made new antivenom scaffolds accessible for researchers. There is currently
no consensus as to the pharmacokinetic properties of an optimised antivenom,
and whether these change depending on the type of venom being treated. To
address this question computationally, we built a compartmental model of
snakebite envenomation and treatment. The model tracks the movement of venom,
antivenom, and neutralised venom through blood and tissue. The model was
parameterised with experimental data from rabbits. It enables user-control of
several treatment scenario parameters and antivenom design parameters
(antivenom size, dose, affinity, and valency).
We have applied our model to explore the impact of different antivenom design
features on treatment outcome. We simulated treatment of two model venoms with
a set of theoretical antivenoms, across a range of treatment time delays.
Global parameter optimisation and global sensitivity analysis show kon to
primarily mediate treatment efficacy. While molecular weight has a negligible
direct impact on treatment outcome, low molecular weight scaffolds can be more
easily designed for optimised treatment, particularly when treatment is
delayed. The same underlying trends are seen for both venom types tested. This
approach can be used to elucidate the dynamics of envenomation-treatment
systems, and inform the development of next-generation antivenoms.