Antibody Based Approaches to cancer therapy 2

which property of payloads make them difficult to conjuage?

high hydrophobicity

give some examples of ADC toxicities caused by payloads

• myelosuppression

• GI toxicity

• ocular toxicity

if ADCs have similar toxicity profiles compared to naked drugs, why is it beneficial to use ADCs?

selectivity of ADCs means that the therapeutic window increases :. less likelihood of getting toxicities

what characteristics of payloads make them desirable for ADC formulations?

• high cytotoxic potency (selectively obtained from antibody attachment means toxicity is targeted towards tumour cells, not healthy cells)

• low ability to cause development of resistance

• poor substrate for cell efflux via p-glycoproteins

• stability in serum during circulation time of ADC

• cost effective synthesis

name some of the mechanisms of action by which ADCs act

• tubulin inhibitors

• DNA interactive agents

describe how tubulin inhibitors work

• mitotic spindle is composed of tubulin → disrupting tubulin disrupts mitotic spindle :. inhibitors blocks ability of chromosomes to segregate :. cannot divide properly :. cells die

• cancer cells divide faster :. more susceptible to these agents

• tubulin in the assembly of the spindle has to both polymerase then depolymerise → inhibitors can either interfere with polymerisation or depolymerisation processes

what are the 2 types of tubulin inhibitors?

tubulin stabilisers and tubulin destabilisers

what do tubulin stabilisers do? give an example

promotes tubulin polymerisation :. stabilises microtubules :. prevents depolymerisation

• e.g. brentuximab vedotin = synthetic aurinstatin

what do tubulin destabilisers do? give an example

interferes with tubulin polymerisation

• e.g. trastuzumab emtansine = synthetic maytansin

what are the different types of DNA interactive agents that can used as payloads?

• interstrand cross linkers

• intrastrand cross clinkers

• DNA cleavage

• intercalation

• mono-adduct

• topoisomerase inhibitors

give an example of a novel linker strategy. how does it work?

light-triggered release technology

• photosensitive linkers that require IR light for linker cleavage

• give ADC to patient and use IR light source to shine light on wherever you want payload to be released (i.e. site of tumour)

• :. have temporal and spatial control over payload release

what are antibody-radionucleotide conjugates? give an example of 1

use radionucleotide as payload conjugate instead of cytotoxic (chemotherapeutic) agent

• combines advantages of using targeted radiation therapy and specific immunotherapy

• e.g. ibritumomab tiuxetan

why are murine antibodies using in antibody-radionucleotide conjugates?

high immunogenicity = rapid clearance from the body :. limits radiation exposure

what are antibody-nanoparticle conjugates?

antibodies conjugates to nanoparticles e.g. liposomes which contain genes or cytotoxic agents

• experimental

• high DARs can be achieved

what is ADEPT?

• (like ADC but in 2 steps)

• first course of treatment: antibody linked to an enzyme is first used to target the enzyme to tumour cells → second antibody selective for the antibody-enzyme conjugate may then be introduced to clear the conjugate from general circulation i.e. unbound antibody :. reducing systemic toxicity

• second course of treatment: prodrug form of cytotoxic agent is then administered which is transformed into the active agent by the antibody-bound enzyme selectively at the tumour site