Exam 3 Dosage Forms for Biologics

Question 1

What are biologics?

Answer 1

medications that are derived from or produced by living organisms

Question 2

What are examples of biologics?

Answer 2

recombinant proteins, peptides, blood factors, vaccines, oligonucleotides, and cell based therapies

Question 3

What are other names for biologics?

Answer 3

biotech drugs, biopharmaceuticals, large molecule drugs

Question 4

What is the importance of biologics?

Answer 4

1. of the top 200 drugs by sales in 2018, 73 (37%) were biologics
2. in 2003, only 5 of the top 100 were biologics → dramatic increase!
3. there are more than 100 biologics on the market, with hundreds more in development

Question 5

In 2018, what is the breakdown of the biologics in the top 200 (73 of them) and their types?

Answer 5

monoclonal antibodies (MAbs) and their derivatives → 35
cytokines → 8
insulins → 9
peptides → 7
vaccines → 7
other → 7 (enzymes, oligos, toxins like Botox, blood factors)

Question 6

What is the largest class of biologics?

Answer 6

monoclonal antibodies (MAbs)

Question 7

What are monoclonal antibodies?

Answer 7

1. very large proteins that have MW of over 150,000
2. interacts with antigens at the antigen binding site
3. CHO is the sugar portion of the molecule and is important for how it’s processed in the body
4. has 4 amino acid chains → 2 light and 2 heavy which are linked by disulfide bonds
5. contains mostly beta sheets, little alpha helices
6. top half of antibody is antigen binding portion and bottom half has biological activity

Question 8

What are some properties of MAbs?

Answer 8

1. glycoproteins, high beta sheet content
2. MW around 150,000 daltons
3. quaternary structure → 2 light chains (L) and two heavy chains (H) linked by SS bonds
4. antigen binding occurs through the variable domain (V) at the complementary determining region (CDR)
5. the constant (C) domain (the base arm of Y) helps determine biodistribution, plasma half life

Question 9

What are some examples of MAbs?

Answer 9

Humira, Herceptin, Avastin

Question 10

What are the five different kind of MAb derivatives?

Answer 10

1. chimeric monoclonal antibody → top is mouse derived and bottom is human derived → example is Remicade aka infliximab
2. humanized monoclonal antibody
3. human recombinant antibody → example is adalimumab aka Humira AND golimumab aka Simponi
4. humanized Fab fragment → example is certolizumab pegol aka Cimzia
5. human recombinant receptor/Fc fusion protein (fusion protein takes stem of MAb and attach to 2 receptors) → example is etanercept aka Enbrel

Question 11

What are antibody drug conjugates (ADC)?

Answer 11

1. a growing class of MAb-based drugs in development
2. combine target specificity of MAb with efficacy of small molecule drug
3. can use MAb fragments rather than whole MAb

Question 12

What are the elements of an ADC?

Answer 12

1. antibody → specific for tumor associated antigen that has restricted expression on normal cells
2. linker → attaches the cytotoxic agent to the antibody (is usually fragile but newer linker systems are designed to be stable in circulation and release the cytotoxic agent inside targeted cells)
3. cytotoxic agent → designed to kill target cells when internalized and released

Question 13

What is the mechanism behind ADC?

Answer 13

takes the green ball (toxin) and links it to the antibody so that it might recognize antigens/receptors on cancer cells → like a trojan horse where it is a toxic molecule to cancer cells

Question 14

What type of formulations are ADCs most typically found in?

Answer 14

freeze dried or lyophilized (since the linker is unstable and fragile)

Question 15

What are some things to know about cytokines?

Answer 15

1. includes interleukins, interferons, erythropoietins (are associated with doping scandals)
2. MW of about 30,000 daltons or less → smaller than MAbs
3. high alpha helix content (4 helix bundle)

Question 16

What are some examples of cytokines?

Answer 16

Neulasta, Epogen, Avonex, Rebif, Humatrope

Question 17

What are insulins?

Answer 17

can be a large peptide or a small protein that contains A and B chain to create a quaternary structure that typically coordinates around a zinc to form a hexamer (example is insulin hexamer)

Question 18

What are some properties of insulins?

Answer 18

1. 5800 daltons MW
2. A chain and B chain linked by SS bonds
3. alpha helical structure (but not highly structured)
4. readily associates to form dimers and hexamers
5. many analogs with altered properties that are designed to give different properties

Question 19

What are some examples of insulin analogs?

Answer 19

1. Lispro insulin (Humalog by Lilly)
2. insulin aspart (Novolog by Novo Nordisk)
3. insulin glargine

Question 20

What are some things to know about insulin lispro?

Answer 20

1. fast acting insulin analog

2. Lys and Pro on C terminus of B chain are reversed, blocking the formation of dimers and hexamers

Question 21

What are some things to know about insulin aspart?

Answer 21

1. fast acting insulin analog

2. Pro on C terminus of B chain mutated to Asp

Question 22

What are some things to know about insulin glargine?

Answer 22

1. long acting insulin analog
2. Asn at A21 mutated to Gly, two Arg added to C terminus of B chain → promotes the self association of insulin which leads to microcrystals
3. microcrystals form on injection, slowly releasing drug

Question 23

What are peptides?

Answer 23

1. short proteins, usually less than 50 amino acids
2. some secondary structure with no higher order structure
3. some with chemical modifications

Question 24

What are some examples of peptides?

Answer 24

1. Victoza (liraglutide)

2. Sandostatin (octreotide) → has moiety on the right that doesn’t look peptide like (looks like a small molecule)

Question 25

What is an example of a peptidomimetic?

Answer 25

Telaprevir (Incevik, Vertex) which is used to treat hepatitis C → has peptide like structure but side chains do not look like peptides which is why it is a peptidomimetic (has lots of nitrogens) → can make crystals

Question 26

What are some things to know about vaccines?

Answer 26

1. have several types → inactivated, attenuated, toxoid, conjugate, subunit 2. differ widely in size and structure 3. can be much larger than other biologics and more complex in structure and composition → typically diverse in molecular structure!

Question 27

What is an example of a vaccine?

Answer 27

Zostavax (a macromolecular construct) which is an attenuated virus vaccine for shingles

Question 28

What are the new biologics such as cell therapies?

Answer 28

1. four CAR-T cell therapies now FDA approved 2. first approval was Kymriah in August 2017 3. engineered T cells for cancer immunotherapy 4. these are the first living drugs → not transplants or small/large molecules → they are actual living cells being administered as drugs

Question 29

What is the mechanism behind CART cell therapy?

Answer 29

cytotoxic T lymphocytes have been engineered to treat cancer → 1. remove immune T cells from the patient's blood → 2. genetic programming to fight cancer cells → 3. multiplied and infused back into the patient → 4. newly programmed CAR-T cells kill cancer cells (patients give blood through leukopoiesis and the T cells from the blood are taken to a facility and engineered to express antigens that recognize the patient's cancer which are then re-infused back into the patient)

Question 30

What are the new biologics such as oligonucleotides?

Answer 30

structures are more common with DNA and RNA since it is a nucleotide (not a peptide or protein)

Question 31

What is an example of an oligonucleotide?

Answer 31

Spinraza (nusinersen) injection which is a modified antisense oligonucleotide 1. used to treat spinal muscular atrophy 2. nucleotide (not peptide) chemical structure 3. has instabilities

Question 32

What are the three types of Covid vaccines that are being developed?

Answer 32

1. protein based 2. viral vector 3. mRNA

Question 33

How is a protein based Covid vaccine made?

Answer 33

spike protein is purified and injected → immune system produces antibody

Question 34

How is a viral vector Covid vaccine made?

Answer 34

spike protein gene is purified → adenoviral vector is injected → body produces spike protein → immune system produces antibody

Question 35

How is an mRNA Covid vaccine made?

Answer 35

mRNA that codes for spike protein is purified and injected → body produces spike protein → immune system produces antibody

Question 36

What is unique about the Pfizer and Moderna vaccines?

Answer 36

they are the first mRNA vaccines/therapeutics (maybe even oligonucleotides but the RNA chain is much longer)

Question 37

What is the dosing for biologics?

Answer 37

usually parenteral (IM, SQ, or IV (even nasally???)) → typically not orally! exception is oral vaccines

Question 38

Why aren't biologics typically given orally?

Answer 38

peptides and proteins can't be given orally because they are digested just like other proteins we eat in our food

Question 39

What are common dosage forms for biologics?

Answer 39

1. solution for injection 2. pen or autoinjector 3. pre-filled syringe 4. lyophilized powder for reconstitution prior to injection

Question 40

What is a summary of biologics?

Answer 40

1. biologics are an important and rapidly growing class of drugs 2. major types of biologics in the top 200 are MAbs, cytokines, insulins, peptides and vaccines (as of 2018) 3. most biologics are administered parenterally 4. major dosage forms for biologics are solutions for injection, pens and autoinjectors, pre-filled syringes, and lyophilized solids for reconstitution