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An Introduction to the Regulatory and Nonclinical Aspects of the Nonclinical Development of Antibody Drug Conjugates

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Abstract

Antibody drug conjugates (ADCs) are promising therapies currently in development for oncology with unique and challenging regulatory and scientific considerations. While there are currently no regulatory guidelines specific for the nonclinical development of ADCs, there are harmonized international guidelines (e.g., ICHS6(R1), ICHM3(R2), ICHS9) that apply to ADCs and provide a framework for their complex development with issues that apply to both small and large molecules. The regulatory and scientific perspectives on ADCs are evolving due to both the advances in ADC technology and a better understanding of the safety and efficacy of ADCs in clinical development. This paper introduces the key scientific and regulatory aspects of the nonclinical development of ADCs, discusses important regulatory and scientific issues in the nonclinical to clinical dose translation of ADCs, and introduces new concepts in the areas of pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation.

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Abbreviations

ADC:

Antibody-drug conjugate

ADME:

Absorption, distribution, metabolism and excretion

ASCT:

Autologous stem cell transplant

BW:

Body weight

BSA:

Body surface area

CNS:

Central nervous system

DAR:

Drug-to-antibody ratio

DM1:

Mertansine; N2′-deacetyl-N2′-(3-Mercapto-1-oxopropyl)-Maytansine

DM4:

N2′-deacetyl-n2′-(4-Mercapto-4-Methyl-1-oxopentyl)-6-Methylmaytansine

EMA:

European Medicines Agency

FcRn:

Neonatal Fc receptor

FDA:

US Food and Drug Administration

FIH:

First-in-human

HER2:

Human epidermal growth factor receptor 2

hERG:

Human Ether-à-go-go-Related Gene

HNSTD:

Highest non-severely toxic dose

ICH:

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

mAb:

Monoclonal antibodies

MMAE:

Monomethyl auristatin E

MMAF:

Desmethyl-auristatin F

MOA:

Mechanism of action

MTD:

Maximum tolerated dose

PBD:

Pyrrolobenzodiazepine

PD:

Pharmacodynamics

PK:

Pharmacokinetics

POC:

Proof-of-concept

PNS:

Peripheral nervous system

SMCC:

Succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate

STD10:

Severely toxic dose in 10% of rodents

TDC:

ThioMAb drug conjugate

TK:

Toxicokinetics

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Author information

Authors and Affiliations

  1. ToxStrategies, Inc., Baltimore, MD, USA

    Janice A. Lansita

  2. Applied BioMath, LLC., Winchester, MA, USA

    John M. Burke & Joshua F. Apgar

  3. ToxStrategies, Inc., 70 SW Century Dr., Suite 100-409, Bend, OR, 97702, USA

    Barbara Mounho-Zamora

Authors
  1. Janice A. Lansita
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  2. John M. Burke
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  3. Joshua F. Apgar
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  4. Barbara Mounho-Zamora
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Correspondence to Barbara Mounho-Zamora.

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Lansita, J.A., Burke, J.M., Apgar, J.F. et al. An Introduction to the Regulatory and Nonclinical Aspects of the Nonclinical Development of Antibody Drug Conjugates. Pharm Res 32, 3584–3592 (2015). https://doi.org/10.1007/s11095-015-1742-y

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  • DOI: https://doi.org/10.1007/s11095-015-1742-y

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