Protein Based Therapies

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21 Terms

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Major Protein-based therapeutic agents

  1. Antibodies

  2. Treatment agents

  3. Vaccines

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Protein-based therapeutic agents include

  • peptide hormones

  • monoclonal antibodies

  • cytokines

  • therapeutic enzymes

  • blood factors

  • vaccines

  • peptide antibiotics

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Protein-based antibodies

  • monoclonal antibodies

  • abciximab/Reopro

  • adalimumab

  • certolizumab pegol/Cimzia

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Proteins as treatment agents

  • IFN-alpha

  • IL-2

  • Insulin

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Protein-based vaccines

  • HBV

  • HIV

  • COVID-19

  • alpha synuclein

  • beta amyloid

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History of protein-based therapy

  • 18th century: albumin from egg white, blood serum albumin, fibrin, wheat gluten recognized

  • protein: word propsoed in 1838 by Berzelius

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1st protein therapeutic other than antibodies

  • insulin

  • purified from animal pancreases

  • administered to diabetes mellitus patients in 1922

  • 1970s: first recombinant protein therapeutic (humulin)

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Development of recombinant DNA technology occured in

  • 1970s

  • PCR (1986)

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Protein-based therapies in pharma industry

  • new drug costs ~1 billion and takes 16 years to develop

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Target of protein drug

  • enzyme/ligand targeted: proteinase convert poly-protein into functional protein

  • targeted-guide synthesis (TGS): peptide to inhibit ABeta aggregation

  • mAb: specifically binding to protein

    • high affinity, high level of therapeutic result

  • Vaccine (protein and peptides): generate antibody to bind the protein

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Major factors affecting protein drugs

  • immune system: antigenicity of the protein, activity of the immune system

    • low antigenicity desired to avoid elevated immune response against drug

  • enzyme or substrate in the body (CYP 450)

  • property of the protein (structures, folding, aggregations-solubility)

  • bioavailability and affinity to the target (protein-protein interactions)

    • high affinity to target and low affinity to non-target desired

  • modification of the protein (phosphorylation, glycosylation)

    • post-translational modification

  • ADME

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Pharmacological activity of protein drugs

  1. replacing protein that is deficient or abnormal

    1. growth hormone

    2. cytokines

    3. neuro-growth factor (GCSF, BDNF)

  2. Augmenting an existing pathway

    1. increase Wnt for neurogrowth

    2. reduce Abeta production

    3. decrease GSK-3beta

    4. reduce p-tau level

  3. Provide novel function or activity

  4. interfering with a molecule or organism

    1. blocking S protein binding to ACE-2 to prevent COVID-19 infection

  5. Delivering other compounds or proteins, such as a radionuclide, cytotoxic drug, or effector proteins

    1. albumin as carrier

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Molecular mechanism of function

  1. specific noncovalent binders (antibodies)

  2. proteins affecting covalent bonds (Enzymes)

  3. others/carriers (human serum albumin)

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Challenges of Protein-based therapies

  1. safety: side effects due to therapeutic proteins could be divided into 2 large groups

    1. interactions with intended targets

    2. interactions with unintended targets (undesirable side effects)

  2. immunogenicity: significant safety/efficacy issue

  3. efficacy

  4. quality: purity of protein therapeutic essential for safety

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CAR-T

  • chimeric-antigen receptor T-cells

  • immunotherapy

  • engineer host T cell to avoid host immune response/rejection

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Proteins vs Small molecule drugs

  • proteins serve highly specific and complex functions

  • proteins are less likely to interfere with normal biological processes

  • proteins are “natural” and often better tolerated/less likely to elicit immune response

  • proteins are effective replacement therapy for certain genetic diseases

  • protein-based clinical development and FDA approval faster than SMD

  • better patent protection for proteins

  • small-molecule drugs have “good geography” (can cross cell membranes) but limited function

  • proteins have more diverse function but cannot get into cells (useless for intracellular targets)

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Solution to overcome challenges of protein and small-molecule based drugs

  • new class of drug

  • synthetic biologics that combine bioavailability of small molecules with the functional diversity of proteins

  • stapled peptides and RIPtides

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Stapled Peptide

  • synthetically locked (stapled) into alpha-helical shape with optimized cross-linking chemistry to mimic the structure found at the interface of many protein-protein interactions

  • interaction domains of proteins, conformationally restrained in such a way that they still retain the active structure

  • main body of protein replaced with hydrocarbon “staple” that keeps the interactive domain in the active conformation without substantially increasing its size

  • taken up by cells via energy-dependent active transport process

  • advantage: many proteins don’t have active sites

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Functional Classification of Protein-based therapies

  1. Group 1 : protein therapeutics with enzymatic or regulatory activity

  2. Group 2: protein therapeutics with special targeting activity

  3. Group 3: protein vaccines

  4. Group 4: protein diagnostics

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Group 1

  • tenecteplase (recombinant protein)

  • used in thrombolysis

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Protein-based treatment for COVID-19

  • peptide of ACE2: design peptide to block spike protein binding

  • spike protein-based vaccine (recombinant protein or peptide)

  • antibody therapy