Antibody immunotherapy Flashcards
Outline the basics of antibodies
Produced by B cells in response to specific antigens
5 classes (G,A,M,D,E)
Monoclonal are made from identical immune cells
Each Fab domain has variable (V) and constant (C)
What are murine therapeutic mAbs (o)
potentially most immunogenic and possibly less effective
What are chimeric therapeutic mAbs (xi)
human constant region with non-human (murine) variable regions
What are humanised therapeutic mAbs (zu)
human constant regions with some complementary determining regions replaced with non-human sequences
What are chimeric/humanised mAbs (xizu)
A combination of both antibodies structure
how are human (u) monoclonal antibodies derived
using transgenic mice or phage display
Explain how monoclonal antibodies are dosed
- Dosed as either FIXED dose or by subject body weight (mg/kg), the frequency of administration is
MAb-dependent - MAbs relatively stable in the circulation and can be given ~once per week or at greater intervals
How do humans receive mAbs
given by IV but some can be given by sub-cutaneously
Evaluate the different routes of administration for mAbs
- IV is optimal administration route for most MAbs due to greater and more rapid bioavailability
- SC administered MAbs are taken up by lymphatic channels and may not reach maximum plasma concentration for several days
- Oral MAbs are large molecules, not highly lipophilic, unstable in GI environment
How do MAbs leave the circulation into tumours
- leaves the vasculature by hydrostatic and osmotic pressure (may differ due to tissues)
- There is complex penetration process into tumours
- Volumes of distribution relatively small
Why might biopsied solid tumours show non uniform distribution of MAbs in tissues
Barriers to inward diffusion of mAbs =
- high interstitial pressure
- poor lumphatic drainage
- leaky vasculature
- hypoxic core
- Binding site barrier hypothesis
What is the binding site barrier hypothesis
MAbs with very high affinity for target Ag will bind to first Ag encountered in tumour and thus accumulate in regions surrounding tumour vasculature
Why might the volume of distribution by relatively small for mAbs
- Indicates distribution restricted to blood and extracellular space compartments
- Low tissue: blood ratio common: 0.1 – 0.5
- Poor CNS penetration: CSF levels only 0.1 to 1% of respective serum levels
How are mAb eliminated
Most mAbs are eliminated by reticuloendothelial macrophages
(half-lives of MAbs are quite variable, from 2 days to several weeks)
Two general clearance pathways –
(i) Linear clearance via nonspecific catabolism
(ii) Target-mediated drug disposition (TMDD, target-mediated clearance)
Explain target-mediated drug disposition clearance
Drugs bind with high affinity to its biological target
= these drug-target complex are internalised and degraded
[membrane target = receptor-mediated endocytes] [Soluble targets = complex often eliminated by RES]
Saturable mechanism because finite amount of target in body
How does protein/target conc effect TMDD saturation therefore elimination of mAbs
- If [protein] < [target]: no TMDD saturation
(Higher CL and shorter half-life) - If [protein] > [target]: TMDD saturation
(Lower CL and longer half-life)
What are the mechanism of action of mAbs (Direct effects of anti-tumour IgG)
- Blocking binding of an activating ligand responsible for the survival of the cancer cell
- Inhibiting dimerization of a receptor, thereby blocking an activation signal
- Inducing an apoptotic signal by cross-linking a receptor
What are the mechanism of action of mAbs (Immune-mediated effects of anti-tumour IgG)
- Mediate antibody dependent cellular cytotoxicity (ADCC) with natural killer cells, monocytes/macrophages or granulocytes acting as immune effector cells
- Fixation of complement can opsonize the target cell and enhance lysis by monocytes and granulocytes
- Complement mediated cytotoxicity - results directly in target cell death through development of a membrane attack complex
Successful mAb-based therapeutics have been based on a number of strategies such as
- Anti-tumour IgG
- Angiogenesis inhibition
- Immune checkpoint blockade
- Radio-immune therapy
- Antibody-drug conjugate
- Chimeric antigen receptor (CAR) T cells
How do anti-tumour IgG work
IgGs that bind to target cancer cells can (A) mediate Antibody dependent cellular cytotoxicityby immune effector cells, induce CMC, or result in direct signaling induced death of cancer cells (e.g. herceptin and rituximab).
Why can blocking immune checkpoint be a strategy to treat cancer using mAb
block inhibitory signals on T cells thereby resulting in a stronger anti-tumour T cell response
How does radio-immune therapy work
Radioimmunoconjugates deliver radioisotopes to the cancers cells
what do antibody drug conjugates do
deliver highly potent toxic drugs to cancer cells
How is antibody based retareting of cellualr immunity carried out ?
- mAb variable regions are used to retarget immune effector cells towards cancer cells using bispecific mAb to recognise the cancer cells AND activating antigen on immune effect cells
- Gene therapy approach where DNA for mAb variable region, fused to signalling peptide, is transferred to T cells making them chimeric antigen receptor T cells
What is Rituximab
1st mAb approved to trwat cancer
- chimeric anti-CD20 mAb
used primarliy in the treatment of B-cell non Hodgkin lymphoma and chromic lymphocytic leukaemia
Outline the benefits of using Rituximab with chemotherapy
[Often used with CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone)]
Progression free survival (PFS) greatly improved in patients with relapsed/resistant follicular lymphoma when rituximab added to CHOP (51.5 vs. 14.9 months, p<0.001, led to the FDA approval
What is Trastuzumab (Herceptin)
A humanised anti HER2 Mab (binds to extracellular domain of HER2 receptors
What is HER2
member of the erbB family of transmembrane tyrosine kinase receptors
= regulates cellular growth, differentiation and survival
What is Trastuzumab used to treat? history?
Major impact on treatment of metastatic HER2+ breast cancer
Low response rates when used alone however when combined with chemotherapy, respponse rates is nealy 70%
What can trastuzumab be used along side
Chemotherapy
Combined with taxane or docorubicin/cylophosphamide
Synergic activity with vinca alkaloids, platinums, capecitabine & gemcitabine
Outline the HERA trial
Phase III trial = After 1 year of adjuvant herceptin treatment as SOC in early stage HER2+ BC
- 24% reduction in risk of death
what are the toxicities surrounding trastuzumab and the contra-indications
Most significant: cardiotoxicity, incl. congestive heart failure
(may be related to HER2 expression on cardiac myocytes)
Synergistic effects when used with anthracyclines, so avoid combining
Measure ejection fraction before therapy, then every 3 months during treatment
Infusion reaction (40%): pre-treatment with acetaminophen, diphenhydramine
Give first dose over 90 minutes, subsequent doses over 30 mins if tolerated
Rare pulmonary complications: avoid in patients with pre-existing lung disease but not lung metastases
What is Cetuximab (Erbitux)
Chimeric anti EGFR MAb
Binds to extracellular domain of EGFR → prevents ligand dependent signalling and receptor dimerisation
Also induces receptor internalisation and degradation, thus inhibiting cell growth and survival, induction ofapoptosis, and decreasedmatrix metalloproteinase andvascular endothelial growth factor production
What is the EGFR
EGFR: epidermal growth factor receptor
EGF signalling pathway drives growth/differentiation of epithelial cells. EGFR belongs to ErB family of transmembrane receptor tyrosine kinases
Why are 250mg/m3 doses of cetuximab needed
Non-linear PK
- Needed to saturate EGRF pools in the body
what are the therapeutic uses of cetuximab
- Metastatic colorectal cancer
(single agent use in EGFR+ metastatic colorectal cancer in patients intolerant to irinotecan/ in combination with irinotecan in patients refractory to/ intolerant to oxaliplatin, irinotecan, and 5-FU) - Non-small cell lung cancer
- Head and Neck SCC
what are the toxicities involved with cetuximab use
- Rash (greater than 50%) pruritus, nail changes, headache, diarrhoea
- Rare but serious: interstitial lung disease, hypomagnesemia
What is Panitumumab
Fully human anti-EGFR mAb
Binds to extracellular domain of EGFR similarly to cetuximab,
What are the therapeutic uses of Panitumumab
Improves PFS in metastatic colorectal cancers with EGFR expressing tumours
Activity in lung and HPV+ head and neck cancer
What are the adverse effects of Panitumumab
Advantage: fully human, so less likely than cetuximab to induce immunogenicity
Toxicity profile similar to cetuximab: rash, pulmonary fibrosis, electrolyte abnormalities
What is Bevacizumab
Humanised anti-VEGF mAb
Binds and neutralises the biologically active forms of VEGF by recognising the binding sites for VEGF on endothelial cells (prevents VEGF from binding to its receptors)
what is VEGF
vascular endothelial growth factor
- important role in tumour angiogenesis
What are the therapeutic uses of bevacizumab
Metastatic colorectal cancer (in conjunction with 5-FU based chemo), Ovarian cancer, Cervical cancer, Non-squamous NSCLC (with atezolizumab, carboplatin and paclitaxel), Metastatic breast cancer (with paclitaxel)
Glioblastoma (single agent following prior therapy)
Unresectable HCC (with atezolizumab)
What are the side effects of Bevacizumab
GI perforations – (Fatal GI perforation in 0.2-1% of ALL patients in trials)
GI fistula in 2% CRC patients and less in others
Delayed wound healing/complications – NOT give within 28 days of surgery - cannot be restarted until wound healed
Hypertension – all grades 34% of trial patients
Proteinuria – all grades 0.7 – 38% of trial patients G4 (nephrotic syndrome 1.4%)
Haemorrhage (including pulmonary haemorrhage or haemoptysis) severe < 5%
Arterial and venous thromboembolism – DISCONTINUE in anyone with an arterial thrombotic event caution in those with venous thrombotic event as at risk of further even if anti-coagulated
Posterior reversible encephalopathy syndrome – RARE reports
What are immune checkpoints
To a group of proteins/pathways found on immune cells. They are hardwired into our immune systems and are essential to maintain self-tolerance
CTLA-4 & PD-1 are the most widely studied
= Many of these immune checkpoints are initiated by ligand–receptor interactions so could be readily blocked by antibodies or modulated by recombinant forms of the ligands or receptors.
what are the 3 subtypes of immune checkpoint inhibitors
CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors
= Can block both CTA4 + PD-1 at the SAME time
Inhibition of which checkpoint causes milder severe immune-related adverse effects
PD-1 vs CTLA-4
Monotherapy = 10% vs 50% develpoed Grade3/4 IrAE
what are the common adverse effects associated with immune checkpoint inhibitors
Rash, Colitis, Hepatitis, Pneumonitis, Thyroiditis
The median time to onset of irAEs differs depending on the type of toxicity, can happen up to 2 years after last dose
How is toxicity of immune checkpoint inhibitors fought
Steriods oral or IV
Sub-specialty teams used
Explain what is known about Radioimmunotherapy conjugated mAbs
- Give names
Used in Haematological cancer
- 131I-tositumomab (Bexxar)
- 90Y-ibritumomab tiuxetan (Zevalin)
Outline what is known about 131 l-tositumomab
Anti-CD20 murine mAb combined with cytotoxic beta-emitting isotope
Highly effective in treatment of relapsed or refractory low-grade, follicular, or transformed B-NHL (effective in rituximab-refractory disease)
Well-tolerated: toxicity primarily haematologic
Outline what is known about 90 Y-ibritumomab tiuxetan
- Anti-CD20 murine mAb combined with cytotoxic isotope
- Sig prolongs time to progression in low grade or transformed NHL
- Use restricted to patients having less than 25% malignant infiltration of bone marrow
- Increased risk of myelosuppression in those having higher infiltration
Outline what is known about antibody drug conjugates
Examples
Antibody-drug (cytotoxic agent) conjugate
ado-trastuzumab + emtansine (T-DM1)
= Kadcyla
Chemotherapy microtubule disrupting agent is delivered to HER2 overexpressing cancers cells
Kadcyla is licensed for the treatment of HER2 +ve metastatic breast cancer following failure of trastuzumab alone
Describe the EMILIA trials
978 patients with HER2+ BC previously treated with trastuzumab and a taxane
- either assigned to (ado-trastuzamab emtansine) or (capecitabine + lapatinib)
An improvement in both progression free survival and overall survival in antibody group
[clinically sig improvement in the overall response rate 44 vs 31]
Outline CAR T-cell therapy
- Blood from patient is removed to get T cells
- CAR T cells are made and grown
- CAR T cells are infused into patients
- CAR T cells bind to cancer cells and kill them
What can be used as Adoptive cell transfer therapies
- Chimeric antigen receptor T cell therapy = uses portions of synthetoc Ab that can recognise specific antigens
- Tumour infiltrating lymphocytes
- Engineer patient T cells to express a specific T-cell receptors which recognise antigens that are inside tumour cells
Why would Tisagenlecleucel Chimeric Antigen Receptor T Cell (Kymriah)
be used
Where all other treatment options have been unsuccessful for relapsed or refractory B-cell acute lymphoblastic leukaemia (ALL).
why would Axicabtagene Ciloleucel (Yescarta) [CAR Tcell] be used
Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after 2 or more systemic therapies
what toxicites are associated with CAR T cells
Cytokine release syndrome = significant fever & hypotension main presenting features; treat with anti-IL6 mAb if severe (e.g. Tocilizumab. Response to therapy can be compromised.)
Neurotoxicity = Often reversible though can be prolonged
