Leukemia, Chronic Lymphocytic 2 (DBM)

Target: B-cell
Action: promotes lysis
FDA: Ofatumumab binds specifically to both the small and large extracellular loops of the CD20402 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre-B- to mature403 B-lymphocyte) and on B-cell CLL. The CD20 molecule is not shed from the cell surface and is404 not internalized following antibody binding.405406 The Fab domain of ofatumumab binds to the CD20 molecule and the Fc domain mediates407 immune effector functions to result in B-cell lysis in vitro. Data suggest that possible408 mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent,409 cell-mediated cytotoxicity.

Target: CD52 antigen
Action: after binding, induces cell lysis
FDA: The precise mechanism by which alemtuzumab exerts its therapeutic effects in multiple490 sclerosis is unknown but is presumed to involve binding to CD52, a cell surface antigen491 present on T and B lymphocytes, and on natural killer cells, monocytes, and492 macrophages. Following cell surface binding to T and B lymphocytes, alemtuzumab493 results in antibody-dependent cellular cytolysis and complement-mediated lysis.

Target: ribonucleotide reductase
Action: inhibitor
FDA: Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite bydeoxycytidine kinase and mono- and di-phospho-kinases to the active 5’-triphosphate metabolite.Clofarabine has affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equalto or greater than that of the natural substrate, deoxycytidine. Clofarabine inhibits DNA synthesisby decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action onribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair throughincorporation into the DNA chain by competitive inhibition of DNA polymerases. The affinity ofclofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosinetriphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNArepair by incorporation into the DNA chain during the repair process. Clofarabine 5’-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of thepro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading toprogrammed cell death.Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro.

Target: CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes
Action: engager of immune cells and/or activator of intracellular death signaling pathways and/or activator of the complement cascade
FDA: Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surfaceof pre B- and mature B-lymphocytes. Upon binding to CD20, obinutuzumab mediates B-celllysis through (1) engagement of immune effector cells, (2) by directly activating intracellulardeath signaling pathways and/or (3) activation of the complement cascade. The immune effectorcell mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependentcellular phagocytosis.

Target: Bruton's tyrosine kinase (Btk)
Action: selective inhibitor
FDA: Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteineresidue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is asignaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK’srole in signaling through the B-cell surface receptors results in activation of pathways necessaryfor B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibitsmalignant B-cell proliferation and survival in vivo as well as cell migration and substrateadhesion in vitro.

Target: T cells and natural killer cells/ pro-inflammatory cytokines by monocytes
Action: activator/inhibitor
FDA: Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Lenalidomide inhibitsproliferation and induces apoptosis of certain hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, and del (5q)myelodysplastic syndromes in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor modelsincluding multiple myeloma. Immunomodulatory properties of lenalidomide include activation of T cells and natural killer (NK) cells, increasednumbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In multiple myeloma cells, thecombination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis.

Target: -
Action: -
FDA: Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring.Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form covalent bonds with electronrichnucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to celldeath via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism ofaction of bendamustine remains unknown.

Target: PI3Kδ kinase
Action: inhibitor
FDA: Idelalisib is an inhibitor of PI3Kδ kinase, which is expressed in normal and malignant Bcells.Idelalisib induced apoptosis and inhibited proliferation in cell lines derived frommalignant B-cells and in primary tumor cells. Idelalisib inhibits several cell signalingpathways, including B-cell receptor (BCR) signaling and the CXCR4 and CXCR5signaling, which are involved in trafficking and homing of B-cells to the lymph nodes andbone marrow. Treatment of lymphoma cells with idelalisib resulted in inhibition ofchemotaxis and adhesion, and reduced cell viability.