mAb Therapies Flashcards
(24 cards)
how many heavy chains does IgG have?
2
how many light chains does IgG have?
2
what are the key PK characteristics of mAb drugs?
good solubility and stability, a long half-life, high selectivity and specificity, and a low risk of conversion to toxic metabolites
what differentiates a polyclonal antibody from a monoclonal antibody?
polyclonal antibodies are produced by multiple B cell clones and target multiple epitopes, whereas monoclonal antibodies are produced by a single B cell clone and target a single epitope
how does the Fc region of IgG contribute to its long serum half-life?
the Fc region binds to the neonatal Fc receptor (FcRn) in acidic endosomes, protecting IgG from lysosomal degradation and recycling it back to the cell surface
why are mAbs typically administered parenterally rather than orally?
mAb are larger, complex proteins that are not absorbed well through the GIT, making oral administration ineffective
what role does antibody-dependent cellular cytotoxicity (ADCC) play in the efficacy of mAbs in oncology?
ADCC involves the recruitment of immune cells, such as natural killer cells, to destroy the antibody-coated cancer cells, enhancing therapeutic efficacy
how does Trastuzumab target HER2+ breast cancer cells?
it binds to the extracellular domain of the HER2 receptor, inhibiting cell proliferation and promoting immune-mediated destruction of cancer cells
what is the MoA of checkpoint inhibitors like Pembrolizumab?
this blocks PD1/PDL1 interaction, allowing T-cells to recognise and attack cancer cells more effectively
what is the process used to generate hybridoma cells for mAb production?
involves fusing B cells from an immunised mouse with myeloma cells to create immortalised cells that produce a specific mAb
what are the limitations of murine mAbs in clinical use?
murine Ab can cause allergic reactions, induce anti-drug antibodies (ADAs) and have a shorter half-life due to weak binding to human FcRn
how do chimeric Abs differ from humanised Abs?
chimeric = approx. 65% human with mouse variable regions, while humanised Abs are approx. 95% human retaining only the antigen-binding regions from the mouse
what are the four main strategies used by targeted cancer therapies?
- inhibit cell growth signalling
- block tumour angiogenesis
- promote cancer cell death
- stimulate the immune system to destroy cancer cells
what are the therapeutic applications of adalimumab (Humira), and how does it function?
used to treat autoimmune diseases like rheumatoid arthritis by binding to TNFa, preventing it from activating inflammatory pathways
how do mAbs achieve high specificity in targeting tumour-associated antigens (TAAs)?
mAbs are designed to bind selectively to specific antigens such as EGFR and HER2, expressed predominantly on cancer cells, minimising off-target effects
what is the role of the mTOR pathway in HER2+ cancer cell survival and how does Trastuzumab interfere with this pathway?
it inhibits apoptosis and promotes cell proliferation; Trastuzumab blocks HER2 signalling which in turn reduces mTOR pathway activation
what is the role of Trastuzumab in cancer treatment?
it targets the HER2 receptor on cancer cells, preventing activation of its intracellular tyrosine kinase and recruiting immune effector cells for ADCC.
what is the clinical challenge with Trastuzumab in breast cancer treatment?
less than 35% of HER2+ patients initially respond due to primary resistance, and about 70% of those who do respond develop acquired resistance within a year
why are mAbs not orally available?
they undergo incomplete absorption when administered intramuscularly or subcutaneously and face nonlinear distribution and elimination
why do mAbs have a non-linear PK?
receptor-mediated endocytosis, limited absorption, and saturation of clearance mechanisms at high doses
what factors influence the half-life of mAbs in circulation?
the half-life is influenced by the binding affinity to FcRn, the rate of elimination through catabolism, and the degree of endogenous antibody responses
what are the clinical benefits and risks associated with mAb therapies like Trastuzumab and immune checkpoint inhibitors?
benefits = targeted action ad lower toxicity compared to traditional chemotherapy, while risks involve immune-related adverse events, such as cardiotoxicity or autoimmune reactions
how does the process of antibody glycosylation affect mAb function and efficacy?
glycosylation influences antibody stability, solubility, and the ability to engage with Fc receptors, thereby affecting both PK and effector functions like ADCC
what are the key challenges in the commercial production of mAbs, particularly regarding manufacturing scale-up?
challenges include ensuring consistent glycosylation patterns, maintaining protein stability, and achieving high yields in mammalian cell expression systems
