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Evolving Strategies for Target Selection for Antibody-Drug Conjugates

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Abstract

Antibody-drug conjugates (ADCs) represent a promising modality for the treatment of cancer. The therapeutic strategy is to deliver a potent drug preferentially to the tumor and not normal tissues by attaching the drug to an antibody that recognizes a tumor antigen. The selection of antigen targets is critical to enabling a therapeutic window for the ADC and has proven to be surprisingly complex. We surveyed the tumor and normal tissue expression profiles of the targets of ADCs currently in clinical development. Our analysis demonstrates a surprisingly broad range of expression profiles and the inability to formalize any optimal parameters for an ADC target. In this context, we discuss additional considerations for ADC target selection, including interdependencies among biophysical properties of the drug, biological functions of the target and strategies for clinical development. The TPBG (5T4) oncofetal antigen and the anti-TPBG ADC A1-mcMMAF are highlighted to demonstrate the relevance of the target’s biological function. Emerging platform technologies and novel biological insights are expanding ADC target space and transforming strategies for target selection.

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Abbreviations

ADC:

Antibody-drug conjugate

ALCL:

Anaplastic large-cell lymphoma

APEX:

Absolute Protein Expression Measurements

BRCA:

Breast invasive carcinoma

CCLE:

Cancer Cell Line Encyclopedia

CD:

Cluster of Differentiation

CEACAM:

Carcinoembryonal antigen

COAD:

Colon adenocarcinoma

CSC:

Cancer stem cell

DLBC:

Diffuse large B-cell lymphoma

DLT:

Dose-limiting toxicity

EBV:

Epstein-Barr Virus

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial-mesenchymal transition

ERBB2:

erb-b2 receptor tyrosine kinase 2 (also known as HER2)

G2/M:

Gap2 / mitosis

GPI:

Glycosylphosphatidylinositol

GTEx:

Genotype-Tissue Expression database

HL:

Hodgkin’s lymphoma

HSC:

Hematopoietic stem cell

iBAQ:

Intensity-Based Absolute Quantification

KIRC:

Kidney renal clear cell carcinoma

LAML:

Acute myeloid leukemia

LUAD:

Lung adenocarcinoma

LUSC:

Lung squamous cell carcinoma

mAb:

Monoclonal antibody

MESO:

Mesothelioma

MMAF:

Monomethylauristatin F

MTI:

Microtubule inhibitor

NSCLC:

Non-small cell lung cancer

OV:

Ovarian serous cystadenocarcinoma

PAAD:

Pancreatic adenocarcinoma

PDX:

Patient-derived xenograft

PRAD:

Prostate adenocarcinoma

PSMA:

Prostate-specific membrane antigen (also known as FOLH1)

RPKM:

Reads per kilobase per million

SKCM:

Skin Cutaneous Melanoma

TCGA:

The Cancer Genome Atlas

T-DM1:

Trastuzumab emtansine

TIC:

Tumor-initiating cell

TMDD:

Target-mediated drug disposition

TPBG:

Trophoblast glycoprotein (also known as 5T4)

TPM:

Transcripts per million

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Acknowledgments

The authors thank Eugene Melamud for assistance with the proteomics data analysis and Chris O’Donnell, Hans Peter Gerber, Kenneth Geles, Paul Rejto and Jeremy Barton for comments on the manuscript.

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  1. Pfizer Inc., Oncology Research Unit, 401 N. Middletown Rd., Bldg. 200-4502, Pearl River, NY, 10965, USA

    Marc Damelin, Wenyan Zhong, Jeremy Myers & Puja Sapra

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Damelin, M., Zhong, W., Myers, J. et al. Evolving Strategies for Target Selection for Antibody-Drug Conjugates. Pharm Res 32, 3494–3507 (2015). https://doi.org/10.1007/s11095-015-1624-3

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  • DOI: https://doi.org/10.1007/s11095-015-1624-3

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