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Engineered Versions of Granzyme B and Angiogenin Overcome Intrinsic Resistance to Apoptosis Mediated by Human Cytolytic Fusion Proteins

  • Christian Cremer
  • Grit Hehmann-Titt
  • Sonja Schiffer
  • Georg Melmer
  • Paolo Carloni
  • Stefan Barth
  • Thomas Nachreiner
Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 6)

Abstract

The use of therapies based on antibody fusion proteins for the selective elimination of tumor cells has increased markedly over the last two decades because the severe side effects associated with conventional chemotherapy and radiotherapy are reduced or even eliminated. However, the initial development of immunotoxins suffered from a number of drawbacks such as nonspecific cytotoxicity and the induction of immune responses because the components were non-human in origin. The most recent iteration of this approach is a new class of targeted human cytolytic fusion proteins (hCFPs) comprising a tumor-specific targeting component such as a human antibody fragment fused to a human effector domain with pro-apoptotic activity. Certain tumors resist the activity of hCFPs by upregulating the intracellular expression of native inhibitors, which rapidly bind and inactivate the human effector domains. Higher doses of the hCFPs are, therefore, required to improve therapeutic efficacy. To circumvent these inhibitory processes, novel isoforms of the enzymes granzyme B and angiogenin have been designed to increase their intrinsic activity and reduce their interactions with native inhibitors resulting in more potent hCFPs that can be applied at lower doses. This chapter summarizes the basic scientific knowledge that can facilitate the rational development of human enzymes with novel and beneficial characteristics, including the ability to avoid neutralization by native inhibitors.

Keywords

Targeted therapy Human cytolytic fusion protein Apoptosis Effector domain Angiogenin Granzyme B Tumor-specific binding domain Natural inhibitor Serpin B9 PI-9 RNH1 

Abbreviations

Å

Angström

ADC

Antibody drug conjugate

ALS

Amyotrophic lateral sclerosis

AML

Acute myeloid leukemia

AMML

Acute myelomonocytic leukemia

APAF 1

Apoptoticproteaseactivatingfactor 1

AV

Annexin V

BID

BH3 interacting domain death agonist

CASM

Computer-aided simulation modeling

CMML

Chronic myelomonocytic leukemia

CNS

Central nervous system

CTL

Cytotoxic T lymphocyte

Cyt c

Cytochrome C

DAPK2

Death-associated proteinkinase 2

dATP

Deoxyadenosine triphosphat

DC

Dendritic cell

DFF45

DNA fragmentation factor-45

DFG

Deutsche Forschungsgemeinschaft

DNA

Deoxyribonucleicacid

DNA PK

DNA-dependentproteinkinase

DNMT2

DNA methyltransferase 2

DPPI

Dipeptidyl peptidase 1

EBV

Epstein-Barr virus

EC50

Half maximal effective concentration

EFRE

European Fund for Regional Development

ER

Endoplasmicreticulum

ETA

Pseudomonas aeruginosaexotoxin A

ETA’

Truncated version of the Pseudomonas aeruginosa exotoxin A

FDA

Food and Drug Administration

GrB

Granzyme B

HAMA

Human anti-mouse antibody

hCFP

Human cytolytic fusion protein

HEK

Human embryonic kidney

hLHR

Human luteinizing hormone receptor

ICAD

Inhibitor of caspase-activated DNase

IFN

Interferon

IL

Interleukin

IRES

Internal ribosome entrysite

LeY

Lewis Y antigen

LPS

Lipopolysaccharide

MOMP

Mitochondrial outer membrane permeabilization

mRNA

Messenger RNA

mRNP

mRNA-based ribonucleoproteins

NKcells

Natural killer cells

NLS

Nuclear localization signal

NRW

North-Rhine Westphalia

NuMA

Nuclear mitotic apparatus protein

PARP

Poly (ADP-ribose) polymerase

PEG

Polyethylene glycol

PI

Propidium iodide

PI 9

Proteinase inhibitor-9

raPIT5a

Rat pituitary gland

RCL

Reactive center loop

RISC

RNA-induced silencing complex

RNA

Ribonucleic acid

RNAi

RNA interference

RNH1

Ribonuclease/angiogen ininhibitor 1

RPMI

Roswell Park Memorial Instiute

rRNA

Ribosomal RNA

scFv

Single chain fragment variable

SDS

Sodium dodecyl sulfate

tiRNA

tRNA-derived stress-induced RNA

TNF

Tumor necrosis factor

tRNA

Transfer RNA

XIAP

X-linked inhibitor of apoptosis protein

XTT

2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide

Notes

Acknowledgements

This work was funded in part by a grant from the Germany province NRW from EFRE “European Fund for Regional Development” under the theme “Europe—Investment in our Future” and by grant BA 1772/18-1 from the Deutsche Forschungsgemeinschaft (DFG). The authors would like to thank Valeria Losasso and Xiaojing Cong for in silico simulations and Richard M. Twyman for critically reading the manuscript.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Christian Cremer
    • 1
  • Grit Hehmann-Titt
    • 2
  • Sonja Schiffer
    • 1
  • Georg Melmer
    • 2
  • Paolo Carloni
    • 3
  • Stefan Barth
    • 1
    • 4
  • Thomas Nachreiner
    • 1
  1. 1.Department of Pharmaceutical Product DevelopmentFraunhofer-Institute for Molecular Biology and Applied EcologyAachenGermany
  2. 2.Pharmedartis GmbHAachenGermany
  3. 3.Computational BiophysicsGermany Research School for Simulation SciencesJülichGermany
  4. 4.Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical EngineeringUniversity Hospital RWTH AachenAachenGermany

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