How to Accelerate and Enhance ADC Therapies

The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
How to Accelerate and
Enhance ADC Therapies
Ross Bemowski, Ph.D., Associate Director API R&D
Jeff Carroll, Team Lead ADC Express

The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

Agenda
1
2
3 ADC Express™ Services
Jeff Carroll, Team Lead
Chetosensar™ Technology
Ross Bemowski, Ph.D.
ADCore Payload Intermediates
Ross Bemowski, Ph.D.

4
Antibody-Drug Conjugate Composition
Specific for a tumor-associated
antigen that has restricted
expression on normal cells.
Designed to kill target
cells when internalized
and released.
Attaches the cytotoxic agent to the
antibody and are designed to be stable in
circulation and release the cytotoxic agent
inside targeted cells.
Payloads
typically are
cytotoxic small
molecules
Antibody
Payload
Linker
 Dolastatins – 40%
 Maytansinoids – 25%
 PBD’s – 10%
Webinar: How to Accelerate and Enhance ADC Therapies

Products to accelerate and enhance ADC drug discovery
and development
5
ADCore Product Line
ChetoSensar™ Technology
Discovery/
Pre-Clinical
cGMP Clinical
Development for
Phases 1 and 2
Phase 3 and
Commercial
ADC Express™ Services
Lead
Candidate
ADC
3
ADC
2
ADC
1
DOLCore™ Intermediate MAYCore™ Intermediate PBDCore™ Intermediate

Payloads Used in ADC Development
75% of Payloads Arise from 3 Commonly Used Classes
 Tubulin inhibitors
 Derived from a sea hare
 5 Commercial ADCs
Dolastatins
Maytansines
 Tubulin inhibitors
 Derived from an African shrub
 1 Commercial ADC
PBD Dimers
 DNA damaging agents
 Derived from streptomyces
 1 Commercial ADC
7

8
Where Do Developers Get these Payloads?
 Purchase commonly used payloads
 Synthesize novel payloads
Clinical / Commercial
Research
 License
 CDMO
 Internally develop/manufacture

Traditional
Approach
Drug companies must currently:
 Find a qualified CMO – potent compounds
 Invest > 5 MEUR per program
 Invest 2 to 4 years for drug development
 Invest in ongoing royalty and licensing fees
 Avoid FTO issues
 Deal with ongoing supply chain, quality, and
regulatory issues
Does a more efficient approach exist?
16 Chemical Steps
9
Historic Pathway to Developing Drug Conjugate Payloads

Solid quality and regulatory platform – DMF/Dossier
Supply chain complexity reduced – Flexibility
Advantages of the payload core platform include
speed to market and FTO - Years
1
2
3
10
Imagine starting a marathon at mile 21…

ADCore Product Line
PBDCore™ Intermediate
11
 PBDCore™ Intermediate can
be used to make diverse and
highly potent PBDs
 Newly launched!
Simplify your Payload Synthesis
DOLCore™ Intermediate
 DOLCore™ shortens
synthesis of dolastatin
payloads to 4 or fewer steps
 Launched 2021
MAYCore™ Intermediate
 MAYCore™ can be
modified to meet your
specific maytansine linker-
payload needs
Versatility
Can be
modified to
meet your
specific
linker-
payload
needs
Speed
Reduce the
number of
synthesis
steps
Reduced-
risk
Supply chain
risk reduction
– Ready
stock
available
High Quality
Chemical
processes
optimized to
ensure
quality
Reg.
Support
Phase
appropriate
regulatory
documents
available
Royalty-free
Royalty-free
license
Exclusivity
Earlier
market
exclusivity of
the
commercial
drug
Saving more
patients lives

DOLCore™ Increases Speed to Clinic and Reduces Risk
Traditional
Approach
Via DOLCore™
Intermediate
16 chemical Steps
3 chemical Steps
12

Diversity in your payload synthesis
PBDCore™ Intermediate: Versatility Your Payload Needs
• PBDCore™ intermediate is a
versatile product that enables
late-stage modifications:
- Protecting groups can be
selectively cleaved under
mild conditions
- Ketone (purple) serves
as a functional handle
for cross-coupling
methodologies
Versatility
PBDCore™ Intermediate
Access diverse PBD Payloads
13

14
 Any linker can be
conjugated to MAYCore™
intermediate
 Low D-ala-MAYCore™
content
 High diastereopurity
maintained in process
Key Features
MAYCore™ Intermediate
MAYCore™ Intermediate: High quality product suitable for all
published maytansine linkers
Problematic impurity controlled

15 Webinar: How to Accelerate and Enhance ADC Therapies
• Only significant conjugatable impurity is D-ala-epimer
• Controlled to <2.5 A% in process
• Typically, <0.4 A% total other impurities
MAYCore™ Intermediate process impurities are well controlled

16
ADCore – Accelerating Your Path to the Clinic
Synthesis Simplified
 ADCore products allow for quick procurement of a cGMP supply of your desired drug linker
High Quality cGMP Intermediates
 Highly pure intermediates made through well defined processes
 Full regulatory support
Ready Now!
 ADCore materials are available now for purchase royalty free
 Contact us for information about free samples

A solution is needed for the hydrophobicity problem
 Requires lowering of
DAR
 Subsequent loss of
efficacy and smaller
therapeutic window
 Side effects
Major modifications needed:
 Drug-to-antibody ratio (DAR)
 Change formulation
 Payload selection
 Conjugation site
 Increased use of co-solvent Project termination
 Additional investments needed
(time, $/€, people)
 Increased development risk
 Potential IP / FTO restraints
Further development
ADC poorly soluble
Implications
Solubility is a technical obstacle for today’s ADC
“I am aware of two Small Biotechs that even
went bankrupt because they could not
solve the solubility issue”
- Tier 1 US-based Univ. professor -
~22% of ADC clinical terminations were
caused by poor ADC solubility = loss of 2 to 3
programs advancing to commercial,
~15B€ loss over 10 years
18

Our Chito-oligosaccharide enhances solubility
Consider it Solved!
19
ChetoSensar™ technology
is a
drug enabler
ChetoSensar™
Technology
Chito-oligosaccharide
Payload (=drug)
Antibody
Linker
19

Incorporating ChetoSensar™ technology (CO) into an ADC
reduces hydrophobicity
0 5 10 15 20 25
m
AU
0
20
40
60
80
100
120
D
AD
1 A, Sig=280,4 R
e
f=o
ff (IS18IS018 2018-01-23 08-05-23_H
IC
18IS0180000003.D
)
10.631
D
AD
1 A, Sig=280,4 R
e
f=o
ff (IS18IS018 2018-01-23 08-05-23_H
IC
18IS0180000010.D
)
11.984
13.928
D
AD
1 A, Sig=280,4 R
e
f=o
ff (IS18IS018 2018-01-23 08-05-23_H
IC
18IS0180000018.D
)
0 5 10 15 20 25
mAU
0
20
40
60
80
100
120
DAD1 A, Sig=280,4 Ref=off (IS18IS018 2018-01-23 08-05-23_HIC18IS0180000003.D)
10.631
12.168
14.141
Hydrophilic
hydrophili
c
Hydrophobic
t/min
ADC
Absorption
Antibody alone
ADC + CO
Antibody alone
CO
20
Hydrophobicity is a key
criteria that influences the
solubility,
permeability and
potency
of a drug
HIC Chromatogram

Many constructs have been prepared
Great flexibility with linkers, payloads and antibodies
Linkers
Disulfide
Cat B
Maleimide
ß-Gluc
Payloads
Dolastatins
Maytansines
Duocarmycin
CBI Dimers
PBD Dimers
SN38
Antibodies
Various IgG formats
Engineered
Bispecific
Conjugation
Technologies
Chemical coupling
Enzymatic coupling
Site specific
Stochastic
21

Chemotherapeutics
Maximum tolerated dose (MTD)
Minimum effective dose (MED)
Maximum tolerated dose
Minimum effective dose
Traditional ADC ADC with ChetoSensar™
Improved potency
no additional side
effects
Possible fine-tuning
-several Payloads
possible
-different Linker
Maximum tolerated dose
Minimum effective dose
Therapeutic
window
MTD/MED
Drug
dose
ChetoSensar™ technology broadens the therapeutic
window
Increased solubility and
superior performance for
Interchain Maleimide
Cat B- MMAE ADC with
ChetoSensar™ was seen
in in-vivo studies
22

ChetoSensar™ ADC achieves tumor regression close to baseline
Efficacy
0
400
800
1200
1600
2000
31 41 51 61 71 81 91
Tumor
Volume
in
mm³
days
Vehicle, PBS
Only vc-MMAE; DAR 4, 6mg/kg
vc-MMAE w/ ChetoSensarTM; DAR 4, 6mg/kg
 With 1/3 of dose, ChetoSensar™ conjugated ADC gives same result as standard ADC
 At same dose, ChetoSensar™-ADC led to rapid and complete tumor regression
 Median results report from a group of 8 mice
Key Takeaways
23
SK-OV-3 Xenograph

ChetoSensar™ achieves tumor regression with proprietary
payload
0
200
400
600
800
1000
1200
1400
1600
1800
2000
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
Tumor
Volume
(mm³)
Study Days
MKN45 Xenograph
 No side effects or body weight loss observed with Duocarmycin
 8 of 10 animal tumor free, no regrowth observed
 ChetoSensar™ successfully used in internal R&D projects
Key Takeaways
Vehicle, PBS
10 mg/kg ADC, without ChetoSensarTM
10 mg/kg ADC, with ChetoSensarTM
24

• Significantly increases hydrophilicity of challenging payloads
• Can be used with a wide selection of linkers, payloads, and
conjugation technologies
• Demonstrated increases in efficacy across multiple ADCs
25
ChetoSensar™ Technology: Consider it Dis-solved!

Approvals have nearly doubled the last 3 years
27
The ADC industry 2022
ADC Approval year linker payload
Mylotarg 2017;2000 AcBut (lysosome cleavable) Calicheamicin
Adcentris 2011 VC Protease cleavable MMAE
Kadcyla 2013 Non-cleavable DM1
Besponsa 2017 Hydrazone cleavable Calicheamicin
Polivy 2019 VC-PAB cleavable MMAE
Padcev 2019 VC-PAB cleavable MMAE
Enhertu 2019 Cathepsine
cleavable
Exatecan
(camptothecin)
Trodelvy 2020 pH sensitive
cleavable, PEG8
camptothecin
Blenrep 2020 Non-cleavable MMAF
Zynlonta 2021 Cathepsine
cleavable PEG8
Tesirine (PBD)
Tivdak 2021 VC-PAB cleavable MMAE
Noticeable increase in different payloads and linkers

28
How can the ADC industry keep accelerating?
The Hurdles
 Optimization of a new ADC requires
− developing a mAb that effectively binds to target and manufactures well
− choosing the appropriate payload that retains efficacy once delivered
− developing linkers that
− impart overall in vivo stability
− help prevent fast clearance to improve pharmacokinetics
− release the payload appropriately at target to retain therapeutic function
Each arm has its own challenges when it
comes to optimization

29
Can we learn from the success of other industries?
Small Molecule Medicinal Chemistry R&D
 thrived in the 90’s when library formats were adopted
 libraries produced dozens of compounds at a time
 enabled Structure Activity Relations (SAR) to efficiently identify lead candidates
But ADCs are much more complex than small molecules
 single point, custom modifications around linkers, payloads, and loading require large
time and money commitments
 changing one component of the ADC could influence/alter the behavior of the others
making predictions challenging

30
How Can ADC ExpressTM Help You With Candidate Selection?
30
mAb1
Lead Candidate
ADC3
/4
ADC2
ADC1
GLP & GMP
(Development,
Clinical &
Commercial)
Customer Our Company
Multiple ADCs
Our services for mAb, drug linker, and ADC conjugation development are fully
integrated to help accelerate your path to GMP and commercial manufacturing
PBDs
Camptothecins
Auristatins
Maytansines
Payloads
Linkers and
Solubility Enhancers
noncleavable
PEGs
cleavable
ChetoSensarTM
Evaluating more combinations should result in better ADCs

Understand the payload to predict which enablers are needed
31
ADC ExpressTM can help with linker selection
Our HPLC hydrophobicity screens can help plan for your library needs.
We can compare your custom linkers to help predict their behavior as well.
Reference
Code
Compound Class RT
RRT vs.
Standard
A irinotecan 10.161 1.21
B auristatin 10.377 1.24
C maytansinoid 13.248 1.58
D DNA chelator (PBD) 13.928 1.66
E maytansinoid (DM1) 14.107 1.68

TmAb+Duocarmycin ADC study with and without solubilizers
32
Hydrophobic characterization of DAR species
0
2
4
6
8
10
12
0 2 4 8
HIC
RT
(min)
Duocarmycin DAR Species
Linker Effect on Duocarmycin
DAR Species
No Enabler Branched PEG 8 Chetosensar
Data from Internal ADC Express Trials; J.Ramsay
Species evaluation can help predict what DAR target to go after.
In this case, the Chetosensar™ DAR 8 shows comparable
hydrophobicity to the native mAb.

33
TmAb ADCs with varying payloads and linkers
Hydrophobic characterization of ADCs
0
2
4
6
8
10
12
Duoc. Cheto-MMAE Cheto-Duoc. Cheto-CBI Dimer PEG8-Duoc
HIC
RT
(min)
DAR Species of Various ADC Combinations
HIC Screen of DAR Species
DAR 4 DAR 8
Data from Internal ADC Express Trials; J. Ramsay
HIC profiling can directly evaluate payloads, enablers and DAR

Ligand ka (1041/Ms) kd (10-4, 1/s) KD (nM) Relative % KD
T mAb ADC PEG4 1.22 1.42e 11.6 52.3
T mAb ADC PEG8 0.88 1.05e 11.9 51.0
T mAb ADC PEG12 2.53 1.66e 6.56 92.5
T mAb ADC PEG24 3.06 3.47e 11.3 53.7
T mAb ADC SMCC 2.56 1.69e 6.60 92.0
RS (T mAb) 1.19 0.721 6.07 NA
 Overall antigen binding activities decreased relative to the unconjugated TmAb
 PEG 12 and SMCC linker activity had neglectable impact on binding affinity
 Data indicated linker size influenced the binding activities for different linkers with similar
DAR using the same payload
 Kinetic data including association (ka), dissociation (kd), and equilibrium dissociation
constant (KD) allows primarily efficacy data with low sample requirement
Surface plasmon resonance (SPR) comparability analysis
Understand binding as early as possible

Work with an experienced CDMO at the start of your program
35
Where to start building an ADC library
ADC Express™ Services can be your partner who
− understands and is experienced with various conjugation
chemistries
− can help design your target ADCs of interest
− knows how to get the right pieces in place
− can quickly generate the appropriate constructs
− has the analytical methods in place to provide reliable
characterization for each ADC
Why guess at which ADC will be the best?
Leverage our expertise to make every ADC of interest and test them
Head-to-head!

Products to Accelerate and Enhance
ADC Drug Discovery and Development
36
ADCore Payload Intermediates
ChetoSensar™ Technology
Discovery/
Pre-Clinical
cGMP Clinical
Development for
Phases 1 and 2
Phase 3 and
Commercial
ADC Express™ Services
Lead
Candidate
ADC
3
ADC
2
ADC
1
DOLCore™ Intermediate MAYCore™ Intermediate PBDCore™ Intermediate

Our Vertically Integrated ADC Supply Chain
St Louis, MO:
 ADC Express™ Services
 ADC Clinical and Commercial
development and production
 Clinical MFG suite
expansion complete in
2022
Madison/Verona,
WI:
 Manufacturing site for ADCore
products/ChetoSensar™
technology
 Linker/Payload development
through commercial production
 65 M € GMP MFG expansion
complete 2022
Martillac, France:
 Cell line development to BDS
 mAb clinical development and
manufacturing
 Commercial MFG ready in
2022
Sheboygan, WI:
 Custom non-GMP starting
materials
Schaffhausen,
Switzerland
 PEG linkers for downstream
conjugation
Bangalore, India:
 Custom non-GMP starting
materials

The vibrant M, SAFC, ADC Express, Chetosensar, Dolcore, Maycore and PBDcore are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are
the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources.
© 2022 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

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