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Macromolecular Anticancer Therapeutics pp 133–161Cite as

Poly-l-Glutamic Acid Anti-cancer Drug Conjugates

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

Abstract

Cytotoxic chemotherapeutic agents are the mainstay of anti-cancer therapy. Improvements in the therapeutic ratio of cytotoxic anti-cancer drugs remain a major unmet need as these agents are limited by toxicity to normal organs and relatively modest anti-tumor efficacy as a result of lack of specificity. Cytotoxic drugs target rapidly dividing cells in normal tissues with similar effects to those in tumor tissue. One approach to overcoming these deficiencies is to chemically conjugate cytotoxic molecules such as paclitaxel to a macromolecular carrier. This creates new chemical entities that enhance distribution to tumor tissues, render hydrophobic agents water soluble, potentially decrease toxicity to normal organs, and enhance efficacy. Our group has focused on covalently linking cytotoxic agents to a macromolecular peptide polymer, poly-l-glutamic acid (PGA). PGA was selected for its large number of potential binding sites, high aqueous solubility, lack of immunogenicity, and its biodegradability. This chapter focuses on the developmental challenges associated with polymer therapeutics, using as an example, CT-2103, generically named paclitaxel poliglumex. Sections are devoted to chemistry, manufacturing, and controls specifically addressing development of characterization methods and release specifications for this complex molecule; preclinical pharmacology and toxicology; pharmacokinetics and metabolism including an interaction with estradiol; and clinical development through Phase III trials. A brief review of a second PGA conjugate with camptothecin, CT-2106, is also included.

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Abbreviations

PGA:

poly-l-glutamic acid

MDR:

multidrug resistance

EPR:

enhanced permeability and retention

CT-2103:

paclitaxel poliglumex

GMP:

good manufacturing practice

DCC:

dicyclohexylcarbodiimide

DMAP:

4-dimethylaminopyridine

CMPI:

2-chloro-1-methylpyridinium iodide

DIPC:

1,3-diisopropylcarbodiimide

DMF:

N,N-dimethylformamide

GPC:

gel permeation chromatography

MALLS:

multi-angle laser light scattering

10-DAT:

10-deacetylpaclitaxel

BacIII:

Baccatin III

10-DAB:

10-deacetylbaccatin III

7-epi:

7-epipaclitaxel

10-DAT-7-epi:

10-deacetyl-7-epipaclitaxel

HPLC:

high-performance liquid chromatography

HSQC:

heteronuclear single quantum coherence

COSY:

correlation spectroscopy

NMR:

nuclear magnetic resonance

DOSY:

diffusion ordered spectroscopy

MW:

molecular weight

MTD:

maximal tolerated dose

AUC:

area under the curve

Cmax :

maximal plasma concentration

IV:

intravenous

ICH:

International conference on harmonization of technical requirements for registration of pharmaceuticals for human use

FOB:

functional observational battery

IHC:

immunohistochemistry

TAMs:

tumor-associated macrophages

CB:

cathepsin B

TWI:

tumor weight inhibition

NSCLC:

non-small cell lung cancer

TGD:

tumor growth delay

RT:

radiotherapy

PS:

performance status

HR:

hazard ratio

CT-2106:

poly-l-glutamic acid gly-camptothecin

HSA:

human serum albumin

Boc-gly-CPT:

bocglycine ester of camptothecin

HOBT:

hydroxybenzotriazole

d-TFA:

deuterated trifluoroacetic acid

SCLC:

Small cell lung cancer

T1/2 :

half-life

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Authors and Affiliations

  1. Cell Therapeutics Inc, 501 Elliott Ave W, 98119, Seattle, WA, USA

    Jack W. Singer, Marc McKennon, Gabriella Pezzoni, Stefano di Giovine, Mara Cassin, Paola de Feudis, Cecilia Allievi, Patrizia Angiuli, Marco Natangelo, Enrico Vezzali & Stefano Fazioni

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  1. Jack W. Singer
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  2. Marc McKennon
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  3. Gabriella Pezzoni
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  4. Stefano di Giovine
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  7. Cecilia Allievi
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Correspondence to Jack W. Singer .

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Editors and Affiliations

  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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Singer, J.W. et al. (2010). Poly-l-Glutamic Acid Anti-cancer Drug Conjugates. 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_4

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  • DOI: https://doi.org/10.1007/978-1-4419-0507-9_4

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