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Antibody–Cytotoxic Compound Conjugates for Oncology

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Macromolecular Anticancer Therapeutics

Part of the book series: Macromolecular Anticancer Therapeutics ((CDD&D))

Abstract

The original rationale underlying the development of antibody–cytotoxic compound conjugates (ACC) was to improve the selectivity of cytotoxic anti-cancer drugs by targeting them to tumors with the help of antibodies. The ACC concept has since matured significantly, following several key advancements: (i) generation of technologies for creating humanized and fully human monoclonal antibodies; (ii) development of conjugatable cytotoxic compounds of sufficient potency to be effective in eradicating tumor cells in an antigen-selective manner; (iii) advances in knowledge and antibody engineering to maximize anti-tumor cell effect or functions; and (iv) optimization of linkers used to conjugate cytotoxic compounds to antibodies in order to achieve both maximal stability of the ACC in the circulation and maximal release of the active cytotoxic component within targeted tumor cells. In this chapter we will focus on our present understanding of what makes an effective ACC for the treatment of oncology patients. We will discuss parameters that are important for the selection of antigen targets, antibodies, cytotoxic compounds, and linkers, and current approaches being taken to further improve the efficacy of ACCs. In addition, we will review preclinical and clinical experiences with the current generation of ACCs.

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Notes

  1. 1.

    Most early studies were done with conjugates of antibodies with approved anti-cancer drugs, hence the term “antibody drug conjugates, ADC.” The field has since advanced in creating conjugates of cytotoxic compounds that were developed specifically for attachment to antibodies and are not approved as anti-cancer treatments on their own. Therefore, the use of the term “ADC” is inaccurate for the current generation of conjugates, and so we have replaced it with “antibody–cytotoxic compound conjugates,” abbreviated “ACC.”

Abbreviations

ACC:

Antibody–cytotoxic compound conjugate

ADC:

Antibody–drug conjugate

ADCC:

Antibody-dependent cellular cytotoxicity

AML:

Acute myelogenous leukemia

CDC:

Complement-dependent cytotoxicity

CDR:

Complementarity determining region

CR:

Complete response

CSC:

Cancer stem cell

DM1:

N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol

DM4:

N-methyl-N-[4-mercapto-4-methyl-1-oxopentyl]-l-alanine ester of maytansinol

FcRn:

neonatal Fc receptor

FcγR:

IgG Fc receptor

FDA:

US Food and Drug Administration

IHC:

Immunohistochemistry

MDR:

Multi-drug resistance

MGBA:

Minor groove-binding alkylating agent

MMAE:

monomethylauristatin E

MMAF:

monomethylauristatin F

MTD:

Maximum tolerated dose

PR:

Partial response

PSMA:

Prostate-specific membrane antigen

SD:

Stable disease

T-DM1:

Trastuzumab-SMCC-DM1

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Acknowledgments

We thank our colleagues, Robert Lutz, John Lambert, Rajeeva Singh, Peter Park, Daniel Tavares, Ravi Chari, Yelena Kovtun, and Carol Hausner for critical reading of the manuscript and Yelena Kovtun for drawing the figures.

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  1. ImmunoGen, Inc., Waltham, MA, USA

    Carol A. Vater & Victor S. Goldmacher

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  1. Carol A. Vater
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  2. Victor S. Goldmacher
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  1. Faculte de, Universite Paris-Sud XI, rue Jean-baptiste Clement 5, Chatenay-Malabry cedex, 92296, France

    L. Harivardhan Reddy

  2. CNRS - UMR 8612, Université de Paris XI, rue Jean-Baptiste Clément 5, Châtenay-Malabry, 92296, France

    Patrick Couvreur

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Vater, C.A., Goldmacher, V.S. (2010). Antibody–Cytotoxic Compound Conjugates for Oncology. In: Reddy, L., Couvreur, P. (eds) Macromolecular Anticancer Therapeutics. Macromolecular Anticancer Therapeutics. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0507-9_9

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