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Antibody-Drug Conjugates and Immunotoxins for the Treatment of Hematologic Neoplasms

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Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 6)

Abstract

The antibody-drug conjugate (ADC) is a unique combination of potent cytotoxic drugs covalently linked to monoclonal antibodies (mAb) through a stable specialized chemical linker. Recombinant immunotoxins, fusion proteins which contain the cytotoxic portion of a protein toxin fused to the Fv portion of an antibody, represent the most promising group of ADCs. Antibody-drug conjugates maximize drug delivery to tumor cells without increasing toxicity to normal cells. There are a number of ADCs in preclinical and clinical developments in haematological malignancies that target CD19, CD22, CD25, CD30, CD33, CD37, CD74, and CD79b. One of them, brentuximab vedotin, is approved for use in Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. This chapter focuses on the use of mAbs or fragments of mAbs attached to cytotoxic agents produced by bacteria or plants, including high-molecular-weight protein toxins and low-molecular-weight chemical entities such as calicheamicin, mytansinoids or auristatin, in the treatment of acute myeloid leukemia, B- and T-cell lymphoid malignancies, Hodgkin lymphoma and multiple myeloma.

Keywords

A-dmDT390-bisFv Brentuximab vedotin Combotox DCDTS4501A DCDT2980S Denileukin diftitox Gemtuzumab ozogamicin Inotuzumab ozogamicin Indatuximab ravtansine Lorvotuzumab mertansine Moxetumomab pasudotox Polatuzumab vedotin SAR-3419 

Abbreviations

ADC

Antibody drug conjugate

ADCC

Antibody-dependent cell-mediated cytotoxicity

AE

Adverse event

ALL

Acute lymphocytic leukemia

AML

Acute myeloid leukemia

ALCL

Anaplastic large cell lymphoma

Ara C

Cytarabine

ASCT

Autologous stem cell transplantation

BCR

B-cell receptor

BV

Brentuximab vedotin

CDC

Complement mediated cytotoxicity

CHOP

Cyclophosphamide adriamycin-vincristine-prednison

CLC

Capillary leak syndrome

CLL

Chronic lymphocytic leukemia

CR

Complete response

CRp

CR with no platelet recover

CTCL

Cutaneous T-cell lymphomas

DFS

Disease-free survival

DLBCL

Diffused large B-cell lymphoma; dose limiting toxicity

DM4

N 2 ′-deacetyl-N 2 ′-(4-mercapto-4-methyl-1-oxopentyl) maytansine

DLT

Dose-limiting toxicity

FL

Follicular lymphoma

FDA

Food and Drug Administration

GO

Gemtuzumab ozogamicin

HCL

Hairy cell leukemia

HL

Hodgkin lymphoma

IO

Inotuzumab ozogamicin

IR

Indatuximab ravtansine

MM

Multiple myeloma

mAb

Monoclonal antibody

MCL

Mantle cell lymphoma

MM

Multiple myeloma

MRD

Minimal residual disease

LM

Lorvotuzumab mertansine

LBL

Lymphoblastic lymphoma

MTD

Maximum tolerated dose

MMAE

Monomethyl auristatin E

MMAF

Monomethyl auristatin F

NHL

Non hodgkin lymphoma

OR

Overall response

PFS

Progression free survival

PK

Pharmacokinetics

PV

Polatuzumab vedotin

PR

Partial response

PTCL

Peripheral T-cell lymphoma

RFS

Relapse free survival

SD

Stable disease

VLS

Vascular leak syndrome

Notes

Acknowledgements

This work was supported in part by the grant from the Medical University of Lodz,Poland (No 503/1-093-01/503-01).

No Conflict Statement

No potential conflicts of interest were disclosed.

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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Departments of HematologyMedical University of LodzLodzPoland
  2. 2.Experimental HematologyMedical University of LodzLodzPoland

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