Carbon-14 Labelled ADCs & Peptides

33 Pages·2014·3.41 MB·English

Carbon-14 Labelled ADCs & Peptides

Dr Sean L Kitson
Investigator of Radiochemistry

[email protected]

www.almacgroup.com
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OBJECTIVE
This Enabling Technology Session will focus on
carbon-14 labelling of ADCs and peptides in
A(D)ME studies
[14C]-ADC [14C]-Peptide
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Radiochemistry
S.L. Kitson, D. Speed, ‘Carbon-14 Labelled API Manufacturing’, Drug Discovery World, Winter 2012/13, 14, 72-77. 4
S.L. Kitson, S.J. Jones, W. Watters, F. Chan, D. Madge, ‘Carbon-14 radiosynthesis of 4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-
(trifluoromethyl)-[4-14C]quinolin-2(1H)-one (XEN-D0401), A novel BK channel activator’, J. Label. Compd. Radiopharm; 2010, 53, 140-146.
ADCs – Biotherapeutic bullets
Cysteine (-SH)
• Targeted Therapy
• Mainly towards oncology
residues
• Growing interest within Pharmaceutical
Industry
Lysine (-NH )
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residues
Potential Advantages:

Peptide linker
• Improved targeting of drug
• Increased tolerability of cytotoxic agent binding site
• Re-investigate failed drugs

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Image Source: C&EN; 2014, 92 (3), 13-21.
S.L. Kitson et al; ‘Antibody-Drug Conjugates (ADCs) – Biotherapeutic bullets’, Chemistry Today, 2013, 31(4), 30-36.
Approved
6%
Ph. III
3%
Maytansines
Ph. II
30% Auristatins
21%
55%
Ph. I
70% Duocarmycins
3% Other
Calicheamicins
9%
3%
30 ADCs in various stages of clinical development
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SOURCE: Adapted from Roots Analysis, London 2013.
ADC - Architecture
Monoclonal Antibody: Specific
for tumour associated antigen on
the surface of target cells. Antigen
has restricted expression in normal
cells
Linker: Attaches the drug to the Drug: Designed to kill target cells
antibody: it must be stable in when internalised and released.
circulation to release the drug in Must be applicable to linker
the target cell chemistry technology
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• A cytotoxic drug is attached to an antibody
using a chemical linker.
• The combined ADC molecule eg T-DM1, is then
Linking
injected into the patient.
• In some breast cancer patients, the tumour
cells are covered with lots of receptors called
HER2.
• The antibody locks onto one of these receptors,
Binding
with drug still attached.
• The cell responds by encapsulating the ADC
and receptor.
• Once inside the cell, the antibody and receptor
Internalisation begin to break down.
• The cell breaks the antibody into pieces which
releases the drug.
• As more copies of the antibody are absorbed,
the drug begins to disrupt the cell, eventually
Release
killing it.
Mechanism of Action: ADCs
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Source: Adaptation from The New York Times (June 3, 2012)
KADCYLA FDA APPROVED IN 2013
HER2-positive breast cancer
14C – Labelling on ‘Linker’ Site 9
ADCETRIS FDA Approved in 2011
Hodgkin lymphoma (HL)
14C – Labelling ‘Drug’ Site 10