Approaches and Tools to Maximize ADC Quality
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Approaches and Tools to
Maximize ADC Quality
Colin McKee, Head of Technical Services
ADC World Conference, Berlin, 2018
This presentation is the work product of ADCBIO, no portion of this presentation
may be copied, published, performed, or redistributed without express written
authority.
Overview • Considerations for ensuring ADC Quality • Lock-Release – Principles – Problem solving in ‘difficult to conjugate’ ADCs • ADCBIO’s manufacturing facility – Capability / Capacity – Expansion
Chemistry and Conjugation Experience
Quality Attributes and Contributing Variables Critical Attributes Variables • Correct DAR • Raw materials • Monomeric • Number of process steps • Robust and scalable process • Choice of process route • High yielding • Aggregation propensity • Very low free drug content • Lot to Lot consistency
Get the basics right….
KADCYLA Like Test & Control Early Engagement simplifies
• Test mAb protein G purified things….
with glycine elution • purification conditions
• Isotype control purchased – citrate/acetate elution
as a Tris solution • formulation buffers
– phosphates, HEPES
ADCETRIS Like Test & Control
• Formulated with Proclin – • Rescue strategies
– re-purify – methods established
Cys protease inhibitor
Problematic by Design
Consider your options…….
DM1 DM1
One Pot
NH2 NH2
Two Step
DM1 DM1
QbD Ideally suited to ADC development
Developing a Robust Process • Past experience, mAb DSP, known parameters, literature, • Screening Design → Fractional or Full factorial design • Develop Process Model and Response Surface • Validate the model → typically one or more gram scale runs
Leveraging Design Space Knowledge
• Changing needs are inevitable
– more material required
– vessel volume constrained
Initially Planned
Proposed this change
Verification runs at lab scale
GMP runs successfulKeep Checking
• Even with DOE and OFAT processes must be continually monitored
Scale DAR (3.6 – 4.4) N
10mg 4.01 10’s
5g 4.01 4
50g 4.04 2
150g 4.13 7
• In Specification but subtle sided (all above centre) variation
• Trisulphide content variation as mAb process scaled
• mAb is a raw material not a product – test it accordinglyOne ADC – Several Challenges
Jeffrey et al, Bioconjugate Chem. 2013, 24, 1256−1263
Drug Removal Issues
Aggregation
Aggregation and Drug Removal IssuesLock-Release Concept
Step 1 Lock Antibody to Resin
Step 2 Conjugate 4 Easy Steps
Step 3 Wash High quality, high purity ADC
Step 4 Release
Traceless locking chemistry - only desired
conjugation events modify the antibodyMinimizing Aggregate Formation
Solution Phase C2 PBD / Cys Stochastic DAR 2.5
High level of soluble aggregate – 11-15min
Evidence of residual toxin linker – 25 min
Lock-Release
Low level of soluble dimer
Removal of residual toxin?Enhanced Drug Clearance
SOLUTION LOCK-RELEASE
A214nm
L0 L1H0 H1 H2 L0 L1H0 H1 H2
A280nm
A330nmScalability
Run No. DAR Mono % [DMA] *1 [MMAE] *2 IC 50*3
LR1 3.5 99.9Lysine Chemistry
• Simplifying ‘KADCYLA like’ processing
Resin
Antibody pH DM1 XS DAR % Monomer
Load
L L L 0.6 99
Trastuzumab M M M 1.6 99
H H H 3.8 99
L L L 0.5 99
Cetuximab M M M 1.4 99
H H H 3.8 98
• No need for pre, linking or post conjugation TFF purificationThiomab Conjugation
Tras V205C (Light Chain) Tras S239C (Heavy Chain)
H
mAb H L
L
PBD H H1
L1 L
L
H
Auristatin H
L H1
L1
L
HLock-Release Potential
01 x 20 cm column = 0.3 grams
40 x 20 cm column = 500 gramsGMP Investment and Facility Location
UK based on Welsh / English Border
• 6500m2 existing footprint
• 7500m2 development land
• Space to grow with your needs
MANCHESTER
LIVERPOOL
Phased development plan
ADCBIO
LONDON • $11m GBP secured for Phase I build
• Follow on funding imminent
19GMP Facility
20GMP Facility
Main Offices
Future
R&D
Laboratory and
Laboratory
Offices
Future Building Expansion
QC Current & Future
Laboratory Plant Space
Warehouse
GMP Future
& Raw
Suites GMP Future Building Expansion
Material
I/II Suite(s)
Sampling
Phase 1 Phase 2 Future
21Design Process and Regulatory Engagement
Operation
Commission
and
Construction Validation
Detailed
Design DEC 2107 SEP 2018
Concept
Design
22Follow-On Investment and Options
• Expansion of BDS capacity
– Facility designed for fast doubling of capacity
• Integrate upstream or downstream
– Feasibility and market assessments for both
• Conceptual challenge to current paradigms
– Can mAb DSP and conjugation be integrated
23Conclusions Think ‘Conjugation’ - Avoid the avoidable - Be aware of your options Develop process knowledge and leverage it - Able to react to changing needs - mAb and Toxin Linker are RM’s Lock-Release is an alternative to solution phase - Versatile - Repeatable - Scalable
Acknowledgements Chemistry Sara Jenkins, Phil Harper Bio Conjugation Amy Hippard, Toni Georgiou, Sebastian Braun, Tracy Lynch, Triin Jurgenson, Jake Luhde-Thompson, Steph Johnson GMP Team Charlie Johnson, Jamie Ferguson, Susi Osborne, Iain McGee, Richard Cartwright, Mike Hughes, Glenys Jones
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