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AML-Selective Apoptosis Induction by Rationally Designed Death Ligand Fusion Proteins

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Targeted Therapy of Acute Myeloid Leukemia

Part of the book series: Current Cancer Research ((CUCR))

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Abstract

In the past decade, antibody-based therapeutics have started to make good on their promise with potent clinical activity in several human malignancies, including acute myeloid leukemia (AML). In this chapter, various classes of antibody-based agents designed to selectively induce apoptotic cell death in AML will be discussed, including naked antibodies, antibody–drug conjugates, and immunotoxins. Moreover, the rationale for exploiting several of the body’s own immune effector molecules for the targeted elimination of AML cells is highlighted. In particular, this involves the use of the death ligand TNF-related apoptosis-inducing ligand (TRAIL). Recombinant fusion proteins in which an antitumor antibody fragment (scFv) is fused to soluble TRAIL proved to be essentially inactive while en route, but gain potent pro-apoptotic antitumor activity after selective binding to a predefined tumor-associated cell surface antigen. The use of death ligand fusion proteins may be of clinical significance in targeted approaches in AML.

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Abbreviations

TRAIL:

TNF-related apoptosis-inducing ligand

sTRAIL:

soluble TRAIL

scFv:

single chain of the variable fragments

MAb:

monoclonal antibodies

CDC:

complement-dependent cytotoxicity

ADCC:

antibody-dependent cellular cytotoxicity

ADCP:

antibody-dependent cellular phagocytosis

NK:

natural killer

FcRn:

neonatal Fc receptor

FLT3:

FMS-related tyrosine kinase 3

bsAb:

bispecific antibodies

MHC:

major histocompatibility complex

BiTEs:

bispecific T-cell engager molecules

MNC:

mononuclear cell

GO:

Gemtuzumab Ozogamicin

VPA:

valproic acid

DT:

Diphtheria toxin

CTCL:

Cutaneous T-cell lymphoma

SCID:

Severe Combined Immune Deficiency

PE:

Pseudomonas exotoxin

ETA:

Pseudomonas exotoxin A

eEF2:

eukaryotic Elongation Factor 2

IL-3Rα:

alpha subunit of the interleukin-3 receptor

CLL-1:

C-type lectin-like molecule-1

RI:

RNAse inhibitor

CsA:

cyclosporine

FasL:

Fibroblast associated cell surface ligand

DD:

death domains

OPG:

osteoprotegerin

RANKL:

Receptor Activator of NFĸB ligand

DICS:

death inducing signaling complex

LSCs:

Leukemic stem cells

DARPins:

Designed Ankyrin Repeat Proteins

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Authors and Affiliations

  1. Department of Surgery/Translational Surgical Oncology, University Medical Center Groningen, Hanzeplein 1/BA44, 9713, Groningen, GZ, The Netherlands

    Edwin Bremer & Wijnand Helfrich

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  1. Edwin Bremer
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  2. Wijnand Helfrich
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Correspondence to Wijnand Helfrich .

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  1. Dept. Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Michael Andreeff

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Bremer, E., Helfrich, W. (2015). AML-Selective Apoptosis Induction by Rationally Designed Death Ligand Fusion Proteins. In: Andreeff, M. (eds) Targeted Therapy of Acute Myeloid Leukemia. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1393-0_8

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