antibody drug conjugates and mRNA vaccines

what are the 3 components of antibody drug conjugates

• monoclonal antibody

• linker

• cytotoxic payload (chemo drug)

what is meant by the drug to antibody ratio (DAR)

number of cytotoxic payloads you have attached to one antibody

why does the use of hydrophobic drugs make the bioprocess of ADCs more complex

hydrophobic drugs tend to produce more aggregates

name 2 examples of ADCs for trastuzumab

TDM-1 and T-DXd

what is the DAR of TDM-1

3.5

what is the DAR of T-DXd

8

what is the basic mechanism of action of ADCs

1. bind to target antigen on cancer cells

2. ADC is internalized and processed

3. drug is released

what are the 3 main mechanisms of the cytotoxic drugs used in ADCs

• microtubule polymerisation inhibition

• topoisomerase 1 inhibition

• DNA alkylation

what are the 2 types of linkers

cleavable and non-cleavable

how are linkers cleaved

via proteolysis, reduction or changes in PH

what are the 2 types of instability related to linkers

linker-drug and mab-linker

name an example of a linker that gives a rapid release of cytotoxic load

maleimide caproyl linker

name an example of a linker which provides a more sustained release of the cytotoxic load

maleimide propionyl linker

what factors may affect toxicity of ADCs

• payload potency

• linker properties

do ADCs improve toxicity

most ADCs have a similar or worse toxicity than the chemo drug alone - have not yet improved safety of anticancer treatment

what are the advantages of mRNA vaccines

• well tolerated

• do not integrate into the host genome

• easily degraded

• mRNA molecules are non-infectious

• production of mRNA is fast and cheap

what is the mechanism of action of mRNA vaccines

1. internalised by endocytosis

2. inside the cytoplasm, ribosomes translate the mRNA into proteins

3. activation of CD8+ T cells

what are the 4 components of mRNA vaccines (excluding mRNA)

• cationic ionizable liquid

• cholesterol

• phospholipid

• PEGylated lipid

why is a cationic ionizable liquid used in mRNA vaccines

interacts with the mRNA, then when it becomes unionized the mRNA will be released

why is PEGylated lipid used in mRNA vaccines

ensures colloidal stability and reduces plasma protein adsorption on the lipid nanoparticle

describe mRNA based dendritic cell vaccines

• has a unique ability to regulate the type of immune response produced

• able to stimulate robust and long-lasting CD8 and CD4 + T cell responses

what is a disadvantage of mRNA based dendritic cell vaccines

obtaining a source of dendritic cells and their ex vivo manipulation is very time consuming

what is the advantage of using the IM route for mRNA vaccines

route is highly vascularised and has less injection site reactions

what the advantage of using the IV route for mRNA vaccines

allows vaccine to reach numerous lymphoid organs leading to robust CD8 + T cell response

what are the 3 types of advanced therapy medicinal products (ATMP)

gene therapy, somatic cell products and tissue engineering

what is meant by autologous

uses patients own cells, which are modified and then reinjected into patient

what is meant by allogenic

uses health donor cells which are injected into the patient

what is meant by a gene therapy medicinal product

contains an active substance which contains recombinant nucleic acid used to regulate, repair, replace, add or deplete a genetic sequence

what is a somatic cell therapy medicinal product

contains cells or tissues that have been subject to substantial manipulation so that the characteristics, functions or properties relevant for the intended clinical use have been altered

what is a tissue engineered product

contains engineered cells or tissues and has properties to regenerate, repair or replace human tissue

what are CAR T cells

• chimeric antigen receptor T cells

• these are genetically engineered T cells designed to recognize and destroy specific cancer cells

describe the process of how CAR T cells work

1. patients T cells are collected

2. T cells are genetically modified to express CAR on surface

3. multiplication of T cells

4. infused back into patient

5. CAR T cell binds to the specific antigen on cancer cells and kills them

what toxicity is associated with CAR T therapy

CAR T cells trigger release of IL-6, leading to cytokine release syndrome