Med Chem II Exam 2 Full Set

(GLP-1 Analog) MOA - Augments glucose-dependent insulin secretion; slows gastric emptying Use - Type 2 diabetes SC, Pen injection *Dose: 30mg once weekly* *t1/2 = 5 days* ADR: *pancreatitis* C/I: *patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2)* *REMS*

Albiglutide

(GLP-1 agonist) MOA - Augments glucose-dependent insulin secretion and slows gastric emptying Use - Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes SC, Pen Injection t1/2 = 5 days (Once weekly dosing) ADRs: Pancreatitis BBW - personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2) REMS

Albiglutide

MOA • Humanized PD-L1 monoclonal antibody • Blocks tumor PD-L1 binding to PD-1and B7.1 (aka. CD80) receptors on T-cell Indication • *Metastatic NSCLC* in patients who have undergone Pt-chemotherapy but with disease progression • *Urothelial carcinoma* in patients who have undergone Pt-chemotherapy but with disease progression.

Atezolizumab

• Humanized IgG1 monoclonal antibody. MOA • *Inhibits VEGF-A* (that stimulates new tumor blood vessel formation, *angiogenesis*) by binding. Bevacizumab binds directly to VEGF to form a protein complex which is incapable of further binding to VEGF receptor sites. Indications • *Metastatic colon cancer in combination with standard chemotherapy.* • *Ovarian cancer* • Originally approved for breast cancer, but the approval was revoked in 2011. • Lack of evidence that it extended life or improved quality of life, and it caused serious adverse effects. Black box warning: GI perforations (because its inhibiting blood vessel growth), surgery and wound healing complications, and hemorrhage

Bevacizumab

(Bone-forming Agents) Appropriate intake of calcium = increases peak BMD and may reduce the overall risk of developing osteoporosis Recommended amounts = Teens - 1300 mg/day Premenopausal women and men - 1000 mg/day Postmenopausal women - 1200 mg/day

Calcium Salts

• Cancer cells produce tumor antigens on their surfaces. • Antigen-presenting cells (APC) (dendritic cells) display these foreign antigens complexed with major histocompatibility complexes (MHCs) on their surfaces • Antigen-bound APCs activate B cells and T cells. • When activated by APC, B cells become plasma cells that make antibodies. These antibodies mark tumor cells for elimination. • T cells activated by APC multiply and seek out and destroy tumor cells bearing the specific tumor antigens. • Activated T cells kill target cancer cells • Dying cancer cells release additional cancer antigens, propagating the cancer immunity cycle • *APCs, B cells, T cells and NK cells interacting with the tumor antigens are the core components of the immune response that work to eliminate cancer cells.* • Cancer can result from compromised immune system. Cancer immunotherapy is aimed at boosting the immune system. Types of cancer immunotherapy • Immune checkpoint inhibitors • Cytokines • Cancer vaccines *Immune checkpoint inhibitors* • Immune checkpoints are *inhibitory pathways* built into the immune system for controlling the duration and amplitude of physiological immune responses in order to minimize collateral tissue damage . For example, PDL1 or PDL2 interaction with PD1 receptor and CD80 or CD86 interaction with CTLA4 receptor. -PDL = program cell death ligand • Tumors co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance particularly against T cells that are specific for tumor antigens. • Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be blocked by antibodies. • Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first checkpoint immunotherapeutics to achieve FDA approval. • Programmed cell death protein-1 (PD1) inhibitors are the second class of checkpoint immunotherapeutics to achieve FDA approval

Cancer immunotherapy

• Cetuximab is a chimeric monoclonal antibody. MOA • *It binds specifically to the extracellular domain of the human EGFR* (ErB-1;HER1) • Indication • Indicated for *K-ras mutation-negative, EGFR-expressing colorectal cancer and for head and neck cancer* in combination with other treatments • In July 2009, a genetic test for the KRAS mutation was approved by the FDA as an indication for Erbitux treatment of colon cancer. *This was the first genetic test to guide treatment of cancer.* In July 2012, the FDA approved a real time PCR companion diagnostic test for KRAS, the *therascreen*1 KRAS test [*KRAS is a proto oncogene of the ras family. KRAS mutation is predictive of a very poor response to cetuximab]*. Black box warning: Infusion reactions and cardiopulmonory arrest (closely monitor serum electrolytes)

Cetuximab

(GLP-1 Analog) *Fusion protein* that consists of 2 identical, disulfide-linked chains MOA - Augments glucose-dependent insulin secretion; slows gastric emptying Use - Type 2 diabetes SC, Pen injection *Dose: 1.5 mg weekly* ADR: *pancreatitis* C/I: *patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2)* REMS

Dulaglutide

(GLP-1 agonist) MOA - Augments glucose-dependent insulin secretion and slows gastric emptying SC, Pen Injection t1/2 = 5 days (Once weekly dosing) ADRs: Pancreatitis BBW - personal or family history of medullary thyroid carcinoma and endocrine neoplasia REMS

Dulaglutide

(GLP-1 Analog) 39 AA peptide - *Resistant to the action of DPP-IV* Pharmacologic effects: *reduces HbA1c levels*; appetite reduction; modest weight loss Use - Type 2 diabetes *SC administration* *t1/2 = 3 hrs* ADRs: *acute pancreatitis* - *No risk of hypoglycemia when in combo w/ Metformin* - *Risk of hypoglycemia when in combo w/ Sulfonylurea* C/I: *pts with a history of medullary thyroid carcinoma* *REMS*

Exenatide

(GLP-1 agonist) Structure • Exenatide is a 39-amino acid peptide analog of GLP-1, isolated from the saliva of the Gila monster (Heloderma suspectum). • It has only 53% homology to human GLP-1, but acts as a full agonist at the GLP-1 receptor! • Resistant to the action of DPP-IV Half-life • It has as an in vivo half-life of approximately 3 hours. (vs 2 minutes of GLP1) Pharmacological effects: • Reduce HbA1c levels in type II diabetic patients on sulfonyl urea • Other pharmacological effects: - Causes appetite reduction - Associated with modest weight loss. Recently it has been shown to reduce liver fat in humans - fatty liver is one malignancy associated with type 2 DM favorable property Indication • Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Dosing • It is administered by sc injection as either a 5 or 10 µg dose using a pen-injector device. It is usually administered twice a day. • An extended release form (Bydureon®) suitable for once weekly sc administration received approval in 2012 Hypoglycemia • There is no risk of hypoglycemia when used in combination with metformin. There is a risk for hypoglycemia when used in combination with a sulfonylurea. AEs • Acute pancreatitis, including some fatal • Black box warning: Exenatide extended release (ER) causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared with controls. Human relevance is not established, but contraindicated in patients with a family history of medullary thyroid carcinoma. same for all drugs in the class • The drug has an FDA-approved Risk Evaluation and Mitigation Strategy (REMS) that the manufacturer is required to follow

Exenatide

• A humanized *antibody-drug conjugate (ADC)*. MoAb is conjugated with *calicheamicin*, a small molecule that breaks double stranded DNA. MOA • Gemtuzumab ozogamicin binds to the *CD33 antigen*. This antigen is expressed on the surface of leukemic blasts in more than 80% of patients with *acute myeloid leukemia (AML).* • The drug binds to CD33 to form a complex. The complex is internalized and calicheamicin is released. The released calicheamicin binds to DNA in the minor groove resulting in DNA double strand breaks and cell death. Indication • *Acute myeloid leukemia (AML).*

Gemtuzumab ozogamicin

Leuprolide (GnRH Agonists) MOA - stimulating the pituitary GnRH receptors, causing an increase in testosterone followed by *down regulation in the pituitary secretions of LH and FSH to the level of virtual castration in males* SC Injection or Implant Use - *advanced prostate cancer*

Leuprolide

Mix of Na salts of T4 & T3 - 4:1 ratio MOA - by *supplying the thyroid hormones in the ratio they are normally produced by the body* Use - replacement or supplemental therapy in patients with hypothyroidism

Liotrix

(GLP-1 Analog) Has the 7-37 AA residues of GLP-1 Use - Type 2 diabetes; *weigh control in pts with BMI>30* *t1/2 = 13 hrs (QD dosing)* *SC administration* ADR: *pancreatitis* C/I: *patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2)* *REMS*

Liraglutide

(GLP-1 agonist) Use - As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; *For weight control in patients with BMI>30* *t1/2 = 13 hrs* *SC injections (Once daily)* ADR: *pancreatitis* BBW: personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2) REMS

Liraglutide

(Amylin Agonist) MOA - delays gastric emptying, suppresses glucagon release, and has a central nervous system anorectic effect via unknown mechanisms IM Use - Type 1 and Type 2 diabetics *Used together with insulin for those who are unable to achieve their target postprandial blood sugar levels on insulin alone*

Pramlintide

(Bone-forming Agents) *Nonhormonal bone-forming agent* MOA - *promotes the proliferation and activity of osteoblasts* Essential: this therapy be coupled with oral calcium supplementation

Sodium fluoride

(Bone-forming Agents) *1st approved bone forming agent* Recombinant human parathyroid hormone 1-34 MOA - *increase the number of osteoblasts* *SC Injection* Use - *postmenopausal osteoporosis; glucocorticoid-induced osteoporosis*; increase bone mass in *men with primary or hypogonadal osteoporosis* who have a high risk of fracture

Teriparatide

From thyroid glands of hogs T4/T3 ratio - 2.5: 1 Disadvantages: - *Protein antigenicity* - Product stability - *Variable hormone concentrations* - Laboratory monitoring of patient

Thyroidglobin

6-Mercaptopurine MOA - Inhibits the de novo biosynthesis of purine nucleotides (AMP and GMP) by *inhibiting glutamine amidophosphoribosyl transferase, the rate-limiting enzyme in the synthesis of these purine nucleotides.* - Incorporates into the DNA and the RNA. • Since the major mechanism of action of mercaptopurine is inhibition of de novo purine nucleotide biosynthesis rather than incorporation of false nucleotides into DNA, there is a lower risk for mutagenesis and secondary malignancy compared to thioguanine. What are the mechanisms of resistance? - *attenuated active uptake via nucleoside transporters and - Deficiency in the activating of HGPRT enzyme* Has multiple active metabolites -5-thioinosine monophosphate -6-thiomethylinosine monophosphate (inhibits AMP and GMP synthesis by inhibiting amidophosphoribosyl transferase) -6-thiomethyinosine triphosphate gets incorporated into RNA and deoxy form into DNA Indication • Used in the treatment of acute lymphatic and myelogenous leukemia. Dosing • It is available in an *oral dosage* form, but absorption can be erratic and is reduced by the presence of food. Side effects • Bone marrow suppression is the major use-limiting toxicity, although the drug can be hepatotoxic in high doses. • *Major metabolizing enzyme is thiopurine S-methyltransferase (TPMT).* *Patients with inherited little or no TPMT activity are at increased risk for severe PURINETHOL toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction.* General: Thiopurine Antimetabolites • The two currently marketed purine anticancer agents are *6-Mercaptopurine* (6-MP, Purinethiol®) and *6-Thioguanine* (6-TG, Tabloid®). They are *prodrugs* and *must* be converted *to ribonucleotides by hypoxanthine guanine phosphoribosyl transferase* (HGPRT) before they can exert their cytotoxic actions. • *Subsequently converted to ribosylated triphosphate derivatives, which can inhibit the de novo synthesis of purines, inhibit DNA replication, as well as get incorporated into DNA and RNA.* • All 3 species are active • Triphosphates gets into DNA

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MOA • *Binds to CD52*, an antigen present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes undergo cellular lysis. Indications • As a second-line therapy for *chronic lymphocytic leukemia (CLL).* For CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. • For *T-cell-prolymphocytic leukemia (T-PLL), an aggressive tumor for which no standard treatment exists.* • Approved for MS also. Off Label uses (Picture) Black box warning: Bone marrow suppression, Infusions reactions, cytopenia, malignancies on FDA REMS program *General: Monoclonal antibodies* • Tumor-specific monoclonal antibodies (MoAbs) *target tumor cell antigens or cell surface receptors.* • MoAbs-antigen complex recruits endogenous immunomodulator and cell-destroying cytokines (e.g., natural killer cells, macrophages) to stop the advancement of the cancer. • The engineering of *humanized or chimeric MoAbs* has significantly attenuated the risk of immunologic responses to the murine-derived proteins found in the early agents. *Humanized antibodies* are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. • However, black box warnings for most MoAb anticancer agents caution against such potentially fatal events as *infusion/ hypersensitivity reactions, cytopenias, hemorrhage, hepatotoxicity, infection, tumor lysis syndrome, cardiomyopathy, and cardiopulmonary arrest.*

Alemtuzumab

Yescarta • CAR-T cell immunotherapy - *a CD19-directed genetically modified autologous T cell immunotherapy* - Patients' T cells are reprogrammed with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. • Indication - *Large B-cell lymphoma, relapsed or refractory after 2 or more lines of systemic therapy* • PK - Anti-CD19 CAR T cells displayed an initial rapid expansion followed by a decline to near baseline levels by 3 months post axicabtagene ciloleucel infusion - Peak levels of anti-CD19 CAR T cells occurred within the first 7 to 14 days after infusion • Boxed Warning - *Life threatening cytokine release syndrome* - Neurological toxicities • Cost Consideration - One time cost of $373,000 • Approved in 2017

Axicabtagene Ciloleucel

MOA • A new class of MoAb known as *bi-specific T-cell engager (BiTE)* that works by linking the CD19 antigen on malignant (and normal) B cells with the CD3 antigen on T cells resulting in T cell-induced cytotoxic action on B cells. Indication • *Acute lymphoblastic leukemia; treatment of Philadelphia chromosome negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia* AEs • Myelosuppression, serious and often fatal infections, hepatotoxicity.

Blinatumomab

Chimeric Antigen Receptor expressing T-cell (CAR-T) therapy - A personalized cancer immunotherapy • T cells are collected from a patient blood via apheresis • T cells are *reengineered in a laboratory to produce CAR T cells.* The T cells are genetically engineered, by introducing DNA into them via a chiral vector, to produce chimeric antigen receptors (CARs) on the surface of the cells. CARs allow the T cells to recognize targeted tumor cells' antigen. • The reengineered CAR T cells are "expanded" (multiplied) • At the treatment center CAR T cells are infused into the patient. Many patients are given a brief course of one or more chemotherapy agents, called "lymphodepletion," before they receive the infusion of CAR T cells. CAR T cells that have been returned to the patient's bloodstream multiply in number. CART-T cells recognize and attach themselves to tumor cells that have the targeted antigen on their surface. • The CAR T cells may *help guard against recurrence.* CAR T cells may eradicate all of the cancer cells and may remain in the body months after the infusion has been completed. The therapy has resulted in long-term remissions for some types of blood cancer. • Called a *"living medicine."*

Chimeric Antigen Receptor expressing T-cell (CAR-T) therapy

• *A murine antibody-drug conjugate (radioimmunotherapy).* MoAb ibritumomab complexed with the chelator tiuxetan, to which a radioactive isotope (either yttrium-90 or indium-111) is added. MOA • *Ibritumomab tiuxetan binds specifically to the CD20 antigen* found on normal and malignant B cells. The CD20 antigen is expressed on B lymphocytes and on > 90% of B-cell non-Hodgkin's lymphomas (NHL). • The antibody binding to the CD20 allows *radiation from the attached isotope (mostly beta emission) to kill the cell and some nearby cells.* • In addition, *the antibody itself may trigger cell death via antibody-dependent cell-mediated cytotoxicity (ADCC),* complement-dependent cytotoxicity (CDC), and apoptosis. Together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells. Indication • *For the treatment of relapsed or refractory B cell non-Hodgkin's lymphoma*

Ibritumomab tiuxetan

MOA • Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a key *inhibitory* cell surface protein on T-cells. • CTLA-4 blocking leads to activation T cells which leads to antitumor activity. • Iipilimumab is a human monoclonal antibody that binds to *CTLA-4 thereby blocking CD80 or CD86 binding to CTLA-4.* Indication • Approved in 2011 for *treatment of unresectable metastatic melanoma.* • Black box warning: Severe immune reactions

Ipilimumab

• L-Asparaginase is an enzyme isolated from Escherichia coli. • The mechanism of action of Elspar (L-asparaginase) is thought to be based on *selective killing of leukemic cells* due to depletion of plasma asparagine. • Indication: Indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with *acute lymphoblastic leukemia (ALL)*. • Side effects: Anaphylaxis and serious allergic reactions, thrombosis, and fulminant glucose intolerance.

L-Asparaginase and Peg-Asparaginase

MOA • Nivolumab is a monoclonal antibody that *blocks the binding of PDL1 or PDL2 with PD1 receptor,* causing anti-tumor response. Indication • *Unresectable or metastatic melanoma* with disease progression following ipilimumab and a BRAF inhibitor . • *Non-small cell lung cancer,* metastatic • So far approved for about 10 cancer types • Currently undergoing clinical trials for a variety of cancers including NSCLC, where it has shown positive results

Nivolumab

• Human monoclonal antibody. MOA • Binds to the extracellular domain of the *EGFR*, preventing its activation. Indication • For the treatment of *EGFR-expressing metastatic colorectal cancer with disease progression despite prior treatment.* • In July 2009, the FDA updated the labels to include information about KRAS mutations (KRAS mutation is predictive of a very poor response to the drug; see Cetuximab) • Black box warning: Dermatologic toxicities, infusion reactions.

Panitumumab

Pembrolizumab MOA • Binding of PDL1 or PDL2 with PD1 receptor leads to inhibition of T cell. Pembrolizumab is a monoclonal antibody that *blocks the binding of PDL1 or PDL2 to the PD1 receptor*, causing anti-tumor response. Indication • *Unresectable or metastatic melanoma* with disease progression following ipilimumab and a BRAF inhibitor • *Non-small cell lung cancer, metastatic* • So far approved for 12 types of cancer • Currently undergoing clinical trials for a variety of cancers including NSCLC, where it has shown positive results. • First approval in 2014.

Pembrolizumab

• A *fully human MoAb* MOA • Binds to the vascular endothelial growth factor receptor 2 (*VEGFR2*) thereby blocking the binding of VEGFR2 to VEGF which is needed for downstream effects of VEGF *angiogenesis.* Indications • Colorectal cancer, metastatic ... • *Gastric cancer*, advanced or metastatic. Single-agent or in combination with paclitaxel. • *Non-small cell lung cancer* in combination with docetaxel. Black box warning. • Risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

Ramucirumab

• Rituximab is a chimeric MoAb. MOA • Rituximab binds specifically to the antigen *CD20 located on B lymphocytes.* *Rituximab destroys B cells, and is therefore used to treat diseases which are characterized by B cell proliferation, or dysfunctional B cells. This includes many lymphomas, leukemias, transplant rejection, and some autoimmune disorders* Indications • *CLL, non-hodkins lymphoma and rheumatoid arthritis* (because there's a lot of B cells in it) • Black box warning: Fatal infusion reactions, tumor lysis syndrome resulting in acute renal failure, mucocutaneous reactions, and leukoencephalopathy.

Rituximab

Kymriah • CAR-T cell immunotherapy • *a CD19-directed genetically modified autologous T cell immunotherapy* - Patients' T cells are reprogrammed with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. • Indication - *Acute lymphoblastic leukemia* (relapsed or refractory) in patients up to 25 years of age • PK - High distribution into bone marrow - Tisagenlecleucel is present in blood and bone marrow and is measurable beyond 2 years • Boxed Warning - *Life threatening cytokine release syndrome* - Neurological toxicities • Cost Consideration - One time cost of $475,000 • Approved in 2017

Tisagenlecleucel

• Tositumomab is a murine IgG2a *ADC*. MOA • Tositumomab covalently binds to radionuclide *iodine-131* and causes cell death. 131I emits both beta and gamma radiation, and it decays with a t1/2 of 8 days. Indication • Relapsed or refractory *CD20-positive, non-Hodgkin's lymphoma* Black box warning • Serious allergic reactions (including anaphylaxis), prolonged and severe cytopenias, and radiation exposure.

Tositumomab

• Trastuzumab is a humanized MoAb. MOA • *Binds specifically to EGFR2* • The HER2 gene is amplified in 20-30% of early-stage breast cancers and has been associated with poor prognosis. Trastuzumab has been shown, in both in vitro assays and in animals, to *inhibit the proliferation of human tumor cells that overexpress HER2.* Indications: • *In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer.* • As a single agent for treatment of *HER2-overexpressing breast cancer* in patients who have received one or more chemotherapy regimens. • HER2 overexpressing metastatic *gastric cancer.* Black box warning: Cardiomyopathy, infusion reactions, pulmonary toxicity.

Trastuzumab