Biologics in cancer Flashcards
HER2 in cancer and targeting it
A growth factor activated RTK. it doesn’t have a binding domain, but is activated upon dimerisation with other HER receptors. overexpression leads to more dimerisation and thus more signalling
Trastuzumab binds to the EC domain of HER2 and prevents activation. leads to endocytosis and downregulation by NK cells. this is antibody-dependent cellular cytotoxicity.
pertuzumab binds to the domain of HER2 that binds to HER3, prevent dimerisation. also leads to degradation by NK
Panitumumab binds to HER1 and prevents activation. Same with Cetuximab ^. also leads to immune mediated degradation (NK cells). panitumumab doesn’t lead to immune-mediated cytotoxicity due to different Ig backbone.
What are nano bodies and example
They are derived from heavy chain only antibodies (from camelids). the variable region of the heavy chain is removed. they end up being about 10 times smaller than antibodies. as such they can reach some areas that are inaccessible to antibodies.
Multiple nano bodies can be combined (multimerisation) to create dual specificity therapeutics, such as BI 836 880, which targets VEGF and angiopoietin II (both angiogenic)
Immune system in cancer treatments and drugs targeting it
NK cells kill tumour cells and clear old cells.
Killer T cells kill damaged cells (such as cancer)
antibodies can be used to direct the immune system to the cancer cells
Many tumour cells “hide” from the immune system by up regulating PD-L1/PD-1 and CTLA-4. PD-1 (receptor, PD-L1 is ligand) leads to exhaustion of T-cells, suppressing the immune response. normal cells use this to prevent immune cytotoxicity.
Pembrolizumab, nivolumab and spartalizumab are antibodies for PD-1 receptor. Pembrolizumab used for triple negative breast cancer.
Atezolizumab and durvalumab are antibodies for the PD-L1, preventing binding. prevents the cancer cells from evading the immune system
Bifunctional and trifunctional antibodies examples
antibodies with 2 or 3 specific binding sites.
Vepsitamab binds to MUC17 found on tumour cells and CD3 on T-cells. MUC17 is over expressed in 50% of gastric cancers. it encodes mucins - proteins in mucus.
Blinatumomab is used for acute lymphoblastic leukaemia. Binds to T-cell CD3 and CD19 on B-cells. Allows T-cells to target malignant B-cells.
Catumaxomab is trifunctional. it targets EpCAM an epithelial cell adhesion molecule expressed on malignant epithelial cells, and to CD3 on T-cells and FcyRs on NK-cells. no longer licensed due to bankruptcy.
Antibody-drug conjugates examples
Trastuzumab emtansine - binds to HER2 and emtansine binds to tubule to prevent microtubule formation - cytotoxic targeted specifically to HER2+ cells.
inotuzumab ozogamicin - inotuzumab binds to CD22+ B-cells. It is then internalised by receptor-mediated endocytosis, where ozogamicin is cleaved and released into the cytoplasm. it is derived from calicheamicin, and binds to DNA in the nucleus causing double-strand breaks leading to inhibition of cell proliferation. used for B-cell-specific acute lymphoblastic leukaemia that overexposes CD22.
