Foundations 2 Exam 3 Material - Monoclonal Antibodies

Define Biologic

a biologically-based drug (drug that is actually a protein, nucleic acid, cell, tissue)

Define small molecule drug

drug with MW under 500Da (most drugs)

Define chassis

a host organism that produces a commodity chemical or pharmaceutical (hamster, cells, bacteria, plants, etc)

What types of biologics exist?

whole tissue biologics, gene therapy, monoclonal antibodies, hematopoietic stem cells, vaccines

Describe whole tissue biologics

used for transplantation or grafting

Describe gene therapy

delivery of artificial DNA to a cell to fix an in-born error of metabolism or autoimmune disorder

Describe monoclonal antibodies

monospecific antibodies (proteins) that bind to a monovalent specific drug target

Define monoclonal antibody (mAb)

structurally unique antibody designed to bind to a specific cell surface target to mimic some aspect of the immune response

Define humanized

antibody from non-human which has domains replaced with human antibody peptide sequence

Define recombinant

derived from splicing DNA from two or more genetic sources

Define murine

derived from mouse antibody

Define chimeric

part mouse/part human antibody

Describe small molecule drugs

low MW, organic/chemical, fewer critical process steps, well-known structure, not often immunogenic

Describe biologic characteristics

high MW, made from live cells/protein (contamination risk), more critical process steps, structure may not be known or may be complex (complicates bio-equivalency), often immunogenic

What is a biological reference product?

original or innovator drug that is the first new chemical entity to be approved by the FDA

What is a bio-similar drug?

biologic product that is approved based on high similarity to reference product, with no clinically meaningful differences in safety or effectiveness

What is an interchangeable drug?

bio-similar to an FDA-approved reference product and meets additional standards for interchangeability; can be swapped without provider approval

What additional requirements are needed for interchangeable classification?

produces same result in any given patient and If given more than once, the risk of safety and effectiveness of switching between bio-Whsimilar and reference product is equivalent to using only the reference product

How do you know if a mAb is interchangeable?

the interchangeable will have same generic name + a dash with extra letters

What is filgrastim?

granulocyte colony-stimulating factor

What is filgrastim used for?

stimulate and differentiate granulocytes in the body; usually for patients on cancer chemotherapy; neutropenia

What is the brand name for filgrastim?

Neupogen

How does filgrastim treat neutropenia?

coaxes the bone marrow to produce more neutrophils

Where is filgrastim produced?

in E.coli cells using recombinant DNA technology

What is familial hyper-cholesteremia?

a congenital illness which results in highly elevated levels of cholesterol

What are the two groups of familial hypercholesteremia?

heterozygous (less severe) and homozygous (severe, higher cholesterol elevation)

What is the genetic mutation for familial hypercholesteremia?

mutations in either the LDL, apolipoprotiein B ligand binding region, or the PCSK9 gene

What is the least common mutation for familial hypercholesteremia?

PCSK9 (2.3%)

What is PCSK9 involved in?

mediating degradation of the LDLR by interacting with the extracellular domain and targeting the receptor for degradation

What upregulates PCSK9?

cholesterol depletion, cholestyramine, statins, sterol regulatory element binding protein

What downregulates PCSK9?

dietary and cellular cholesterol, long-term fasting, bile acids

Where is PCSK9 primarily produced?

liver, kidney, intestine

In the case of PCSK9 gain of function, what happens?

less LDLRs

In the case of PCSK9 loss of function, what happens?

More LDLRs

what is the target for LDL cholesterol?

less than 100 mg/dL

Patients with mutations in the PCSK9 gene have virtually ________ circulating levels of PCSK9 in the blood

no

What does PCSK9 stand for?

proprotein convertase subtilisin/kexin type 9

What does PCSK9/NARC1 bind to?

the LDL receptor, causing it to be down-regulated and degraded; causes the LDL receptor to not be available to bind LDL and results in elevated cholesterol levels

Where is PCSK9 found and what is it a target for?

circulates outside of the cells in the bloodstream, viable target for mAbs

How doe PCSK9 mAbs work?

decrease concentration of active NARC1 in bloodstream; bind to PCSK9 and prevent its binding to the LDL receptor, keeps LDL receptor open for LDL to reduce elevated LDL levels

How do statins work?

block the synthesis of cholesterol and by up-regulating LDL receptors; block HMG CoA reductase

How often are PCSK9 inhibitors received?

every 2 to 4 weeks

What is a PCSK9 inhibitor?

Alirocumab/Praluent and Evolocumab/Repatha

Which PCSK9 inhibitor is indicated for patients with heterozygous hypercholesteremia or clinical atherosclerotic CVD?

alirocumab

What PCSK9 inhibitor is indicated for homozygous and heterozygous hypercholesteremia?

evolocumab/repatha

What PCSK9 can be used as an add-on for patients already taking the maximally tolerated dose of statins?

Alirocumab

What occurs in rheumatoid arthritis?

The immune system attacks NORMAL tissue in the synovial membrane; factors are released to promote tissue destruction, increase blood flow, and result in cellular invasion of synovial tissue and joint fluid

Describe the pathogenesis of the inflammatory response

antigen presenting cells process and present antigens to T-cells; T-cells may stimulate B-cells to produce antibodies and osteoclasts are stimulated to destroy bone; Macrophages are activated and stimulate osteoclasts and T-cells to promote inflammation via IL-17; Macrophages stimulate fibroblasts via TNF-alpha to produce MMP to degrade bone matrix

What are some RA risk factors?

ages 15-45; women, T-cell major histocompatibility complex, HLA-DR4 and HLA-DR1 antigens in MHC are risk

What is plaque psoriasis?

dermatologic disease involving red scaly rash due to Th1 cell-mediated immunity and release of cytokines (like TNF-alpha)

Describe TNF-alpha in plaque psoriasis

key player; produced in WBCs like macrophages and T-cells, as well as skin keratinocytes and dendritic cells; elevated TNF-alpha in pts with active psoriasis

What does TNF-alpha release cause?

extensive inflammation and formation of psoriatic plaques

What is the MOA for TNF-alpha inhibitors?

bind soluble and membrane-bound TNF-alpha and inhibit its pro-inflammatory effects

What surface receptors do TNF-alpha bind?

p55 and p75

How do TNF-alpha inhibitors work for psoriasis?

block TNF-alpha from causing keratinocyte invasion, reduce inflammation, and decrease vascular adhesion; psoriatic lesions will improve

How do TNF-alpha inhibitors work for Rheumatoid arthritis?

block TNF-alpha from causing inflammation and substantial remodeling of the synovial tissue; joint damage can be arrested

Describe some adverse effects in TNF-alpha inhibitors

small risk for increased infection due to immunosuppresive effect, especially for Tb; contraindication for CHF, can cause MS, slight increase in lymphoproliferative cancer due to role of TNF-alpha in killing cancer cells

What TNF-alpha inhibitor is chimeric?

Infliximab/Remicade

What TNF-alpha inhibitor is a TNFR2 fusion protein (made up of 2 p75 soluble TNF receptors with an Fc fragment of human IgG)?

etanercept/Enbrel

What TNF-alpha inhibitor is fully humanized?

adalimumab/humira

How does etanercept work?

binds TNF and inhibits it from binding to cell surface receptors that would lead to activation; binds soluble and membrane bound TNF

How is etanercept given?

Sc once (50mg) or twice (25mg) weekly

How does infliximab work?

1. binds to TNF and prevents it from binding cell surface receptors

2. complement-fixing antibody and can induce cell-mediated lysis when bound to surface TNF-alpha (lysis of cells involved in inflammatory response)

* requires/suggested methotrexate co-administration**

What are some adverse events seen in infliximab use?

neutralizing effect due to anti-mouse IgG atb produced, infection, malignancies

How does adalimumab work?

1. binding TNF

2. Inhibiting TNF binding to cell surface receptors (can cause complement induced cell mediated lysis like infliximab)

What are some advantages to adalimumab compared to etanercept and infliximab?

humanized so no neutralizing atb production, does not require methotrexate co-administration

What are some human antibodies to TNF-alpha

Golimumab/Simponi and Certrolizumab/Cimzia

What does EGFR stimulate?

GTP binding to RAS

What is EGFR?

epidermal growth factor receptor; part of the ErbB/HER family of receptor tyrosine kinases

What is HER1?

EGFR

What happens when EGFR is activated?

receptors act via tyrosine kinases and mediate cell proliferation and differentiation

What does EGFR play a role in

embryonic development and stem cell renewal; replenish skin, liver and gut cells due to normal wear and tear

Define protooncogene

normal somatic gene that can be mutated to activate cancer pathways

Define oncogene

mutated protooncogene that can activate cancer pathways

EGFR is implicated in what cancers?

colorectal, head and neck and lung cancers

HER2 is implicated in what cancers?

breast, prostate, bladder, and ovarian cancers

What do EGFR truncations and deletions lead to?

development of different cancer or cancer processes like differentiation, proliferation, metastasis, and cell survival

Where do EGFR mAbs bind?

extracellular domain, which prevents tyrosine kinase auto-phosphorylation and prevents cell proliferation, killing the cancer cell

What do mAbs therapies for HER1/EGFR do?

target extracellular domain of EGFR/HER1 to block auto-phosphorylation; competitively inhibit endogenous ligand binding

Inhibiting EGFR auto-phosphorylation causes what to happen to the receptor-antibody complex?

internalization

What are the EGFR inhibitor mAb drugs?

Cetuximab/Erbitux and Panitumamab/Vecitibix

What is cetuximab indicated and approved for

metastatic colon cancer and squamous cell carcinoma of the head and neck

EGFR oxer-expression is implicated in nearly all of what cancers?

squamous cell carcinoma head/neck cancers

What type of mAb is cetuximab?

chimeric mAb

What type of mAb is panitumumab?

fully humanized anti-EGFR mAB

What is panitumumab especially used for?

metastatic colorectal cancers

If a patient does not respond to irinotecan, what may be an alternative?

cetuximab; (indicated for irinotecan refractory stage 3 metastatic colon cancers)

Only what patients respond to cetuximab and panitumumab?

patients with wildtype KRAS

KRAS mutations downstream of EGR render anti-EGFR treatment ______

ineffective

What does a KRAS mutation cause?

constitutive expression of the Ras-Raf-MAPK pathway, regardless of EGFR activation (keeps Ras-GTP/ON)

(T/F) HER2 has no known binding ligands

True

What is the preferred dimerization partner with other HER family receptors?

HER2

What is the primary mechanism of HER2 gene overexpression?

HER2 gene duplication

What are the two anti-HER2 mAbs?

Trastuzumab/Herceptin and Pertuzumab/Perjeta

What type of mAb is trastuzumab?

humanized IgG1 mAb that inhibits proliferation of tumors that over-express HER2

What is the MOA for trastuzumab?

1. causes receptors to be internalized into endosomes, blocks signaling pathways

2. Antibody-dependent cell cytotoxicity; NK drawn to herceptin bound HER2, NK cells eat cancer cells

Describe trastuzumab resistance?

resistance is usually due to mutations in HER2 or change in expression

What type of mAb is pertuzumab?

recombinant humanized

How does pertuzumab work?

1. binds to dimerization domain of HER2 extracellular domain

2. inhibits heterodimerization of HER2 with other ER receptors

3. Pertuzumab-boudn HER2 targeted by NK cells, NK cells eat cancer cells

Can pertuzumab and trastuzumab be used together?

Yes, due to different binding sites can be used as combo therapy