12-1: 1/12 - Targeted Therapies

Monoclonal Ab's: act extracellularly

Tyrosine kinase inhibitors: small molecules that act intracellularly

Ideal target is:
-macromolecule crucial to malignant phenotype

-cell-surface Ag that upon binding a MAc will internalize by endocytosis and facilitate tumor cell killing

-Ag not expressed sig in vital organs and tissues

-Correlated w/clinical outcome

Drug in which a specific diagnostic test must be performed in order for pt to be considered eligible for tx.

Presence of Phil chromosome (BCR-ABL) gene to identify CML

Overexpression of HER2/Neu protein or amplification of HER2 gene

EGFR overexpression

Humanized MAb's are developed in non-human species but with protein sequences modified to match those of humans.

Humanizing a MAb decreases immunogenicity, neutralizes Ab response and symptoms of allergy and anaphylaxis.

-IgG kappa anti-CD20 Mab (only affects B cells! Only B cells have CD20!!)
Tox:
Infusion reaction (hypoxia, pulmonary infiltrates, MI, cardiogenic shock)
Tumor lysis syndrome

-B-cell Non-Hodgkin's Lymphoma

-Leads to apoptosis, Ab-dependent cell cytotoxicity, and complement-mediated cytotoxicity

Strategy that optimizes efficacy of anti-CD20 MAb by cross-linking MAb to radioconjugate.

Radionucleotide enhances cytotoxicity of MAb against target cells and produces higher response rates than Rituximab.

Iodinated murine MAb against CD20

Indicated with relapsed or Rituximab refractory NHL

Tox:
Infusion reaction
Prolonged cytopenias
Mucocutaneous reactions

Radioconjugated MAb for relapsed or Rituximab refractory NHL

Tox:
Infusion rxn
Prolonged cytopenia
Mucocutaneous rxns

Tyrosine Kinase Inhibitor

Pts with Phil Chrom (BCR-ABL)--CML

Binds VEGF and prevents interaction with receptors (dec'd endothelial cell prolif, dec'd BLOOD VESSEL formation!)

Tox:
GI Perforation
Poor wound healing
Bleeding
HTN

MAb that binds EGFR and prevents interaction with its receptors

Small molecule that inhibits phosphorylation of tyrosine kinases

Binds to HER2 and prevents downstream signaling (dec'd cell growth/prolifern)

Tox: Cardiomyopathy (!), transfusion reaction

Trastuzumab