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PK/PD and stability of ADCs
Sanela Bilic, PharmD, MBA
CL Davis Foundation
Workshop:“Toxicologic Pathology and Preclinical Development of
antibody drug conjugates”
Disclaimer:
No Novartis data was used in this presentation
Thoughts and opinions that will be shared during this
talk are based on the available literature as well as my
experience gained by working on ADCs
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The era of ADCs
Initiation of brentuximab
vedotin Phase III AETHERA
Trial, April 2010
Brentuximab vedotin BLA
received
February 28, 2011
GO voluntary withdrawn from
market, June 21, 2010
Initiation of brentuximab vedotin
Phase I HL, January 2010
2011 FDA
approval of
brentuximab
vendotin
2000 FDA approval
of gemtuzumab
ozogamicin (GO)
1980s use of
ADCs in
clinical trials
1960s first use of
ADCs in animal
models
1900s Paul Ehrlich
introduced the concept
of “Magische Kugel”,
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2013 FDA
approval
of Kadcyla
2013 Over 20 new ADCs
undergoing clinical
development (phase I-III)
Why ADCs? What's the rationale?
Magic bullet story continues
 Arming antibodies with cytotoxics allows for increased synergy
 High potential for improved efficacy and lower toxicity
 Highly complex development:
• Regulatory
• Manufacturing
 Insights gained during previous and current ADC development are
Concentration
aiding in our ability to bring the new ADCs to light
Toxicity
Efficacy
Inefficacy
Cytotoxic
Toxicity
Efficacy
Inefficacy
ADC
John R Adair et al. Antibody-drug conjugates – a perfect synergy. Expert opinion Biol. Ther. 12:9 1191-1206 (2012)
Alain Beck et al. The next generation of antibody-drug conjugates comes to age. Discov Med 10:53, 329-339 (2010)
Therapeutic
index
Proof of concept
ADC More Efficacious than Free Cytotoxin in Mice
MMTV-HER2 Fo5 mammary tumor
(HER2-positive, trastuzumab-insensitive)
1500
Vehicle
Mean Tumor Volume (mm3 )
+/- SEM
DM1
Trastuzumab-mertansine
15 mg/kg, 817 µg/m 2
Trastuzumab 15 mg/kg
Trastuzumab 15 mg/kg + Free DM1 817 µg/m2
1000
Free DM1 817 µg/m2
Free DM1 (near MTD) 1947 µg/m2
500
Free DM1
(cytotoxin)
T-DM1 (ADC)
0
0
IV Dosing
5
10
15
20
25
30
Day
Parsons et al, AACR (2007); Slide adapted from Melissa M. Schutten 2012 presentation
Considerations in the Design of ADCs
Successful ADC is dependent on 3 components
Monoclonal
Antibody
•
•
•
•
•
Target expression and selectivity
Chimeric, humanized, fully human
Limited normal tissue expression
Internalization/Trafficking
Conjugation sites, Immunogenicity
Payload
•
•
•
•
•
Cytotoxic potency
Amenable to linker chemistry
Stability (circulation, lysosomes)
MOA
Bystander effect
Linker
• Stability in circulation
• Selective intracellular release of
biologically active drug-enzymatic
cleavage mAbs degradation
ADC pharmacokinetics are dependent on all three components
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Review of mAb/ADC PK/PD
 The PK and PD of therapeutic mAbs/ADCs are quite
complex, being dependent on both the structure of the
antibody and the specific antigen target
 Being that ADCs are directed against cell-surface antigens,
more then likely will exhibit nonlinear PK behavior
 There are numerous influences that need to be considered:
• Receptor shedding, the patient disease state and the physiology of
the system being targeted
 The PD of most mAbs/ADCs appears to be best described
using indirect response type models
 Conducting PD evaluations requires a clear understanding
of the interaction of mAb/ADC with the target
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Small Molecules and Therapeutic Antibodies
Small molecules
Antibodies
ADCs
300-500 Daltons
~ 150,000 Daltons
~ 150,000 Daltons
LC/MS/MS
ELISA, Gyros,
LC/MS/MS
ELISA, Gyros,
LC/MS/MS
Total or free IgG
Total IgG, ADC, free
toxin, immunogenicity
Oral, parenteral
Parenteral
Parenteral
Distribution
Vary, binding implies
distribution
Small, binding implies
clearance
Small, binding implies
clearance
Clearance
Hepatic/extra-hepatic
metabolism
Renal/bile elimination
Relatively rapid clearance
Basal catabolism
Receptor-mediated CL
IgG level-dependent
Renal/bile -uncommon
Relatively slow
clearance
Basal catabolism
Receptor-mediated CL
IgG level-dependent
Renal/bile -uncommon
Relatively slow
clearance
Varies, usually independent
of PD
2-compartment
behavior
Non-linear PK
Dependent on PD and
physicochemical
properties
2-compartment
behavior
Non-linear PK
Dependent on PD and
physicochemical
properties
MW
Analytical
assay
Dosing
PK
Free or bound drug
Small Molecules and Therapeutic Antibodies
Pre-clinical PK
model
PK DDI
Purity
Impurity
Immunogenicity
Toxicity
Small
molecules
Antibodies
ADCs
Multiple species
Limited number of species due
to limited cross reactivity
Limited number of species due
to limited cross reactivity
Common via enzyme
induction/inhibition,
etc
Not as prominent as small
molecules, but there
Not as prominent as small
molecules, but there. Additional
risk due to payload/small
molecule component
High pure
May be heterogeneous
May be heterogeneous
Well characterized,
often related to toxicity
Difficult to characterize,
Difficult to characterize,
may interfere with PK and
quantitation, often related to
immunogenicity
may interfere with PK and
quantitation, often related to
immunogenicity
Generally not
immunogenic
May be immunogenic
May be immunogenic, higher
risk if immunogenic
Either target-related or
non-target-related
May be exaggerated, prolong
or delayed target related
On target and off target toxicity
will be exaggerated, prolong or
delayed target related
Bioanalytical strategy
Multiple pharmacokinetic assays
Gorovits, Alley, Bilic et al.
 Antibody–drug conjugate analytes.
• (A) Example of a heterogeneous antibody–drug conjugate (ADC) reference standard in vivo and the potential
theoretical analytes;
• (B) conjugated antibody, where at least one drug is present;
• (C) antibody-conjugated drug;
• (D) total antibody, includes conjugated and unconjugated antibody;
• (E) naked antibody, includes fully deconjugated ADC (i.e., drug-to-antibody ratio 0);
• (F) small-molecule catabolites.
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• The analyte mixtures B–F are defined by gray areas to indicate the parts of the ADC structure that would not be fully
measured by the respective assay and colored areas to indicate information that would be fully determined.
Pharmacokinetic characterization
Cross reactive molecule vs non cross reactive molecule
Genentech Kadcyla Data
 With this simple comparison, Genentech scientists nicely
showed the impact of specific target binding and lack of it
on pharmacokinetic profile
• Dose proportional PK of Kadcyla in rats (no specific binding/no cross
reactivity)
• Non-linear PK in cyno due to cross reactivity/specific binding
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Assessment of initial stability of ADCs
 Assessment of the PK differences observed with comparing total vs
ADC PK profile
Concentration (ug/mL)
Concentration (ug/mL)
Total
ADC
Time (days)
Time (days)
 Higher DAR and impact on stability


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In B.Bender et al publication, PK of
different DAR species was
characterized in monkeys
The higher conjugated DAR moieties (≥
3 DM1/trastuzumab) deconjugated
faster than lower conjugated DAR
moieties
B.Bender et al
Slower Drug Deconjugation With Uncleavable Linker
Concentration (µg/ml)
Single IV dose 20 mg/kg ADC
Total Ab
Uncleavable
linker
Cleavable linker
Days post dose
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Polson, et al., Cancer Res., 69(6), 2009
Slide adapted from Melissa M. Schutten 2012 presentation
More Stable Linker Reduces Systemic Toxicity of ADC in Rats
Change in bodyweight (grams)
Single IV dose given on Day 1 :


CD22-DM1 with
cleavable
linker
Days post dose
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Polson, et al., Cancer Res., 69(6), 2009 Slide adapted from Melissa M. Schutten 2012 presentation
On and off target pharmacodynamics
Mechanism of Action
On-Target
Toxicity
Tumor
Skin
Blood Stream
Off-Target
Toxicity
On-target action
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(Therapeutic effect)
Conclusions
 ADCs are:
• Disease-targeted drug constructs
• One of the most emergent and exciting new classes of
oncology compounds
• Complex drugs with complex characterization
- Target antigen, antibody type, linker technology and payload
mechanism/potency
 Reductions in unwanted toxicity are most likely to be
achieved by close attention and optimization of linking
technologies and stability
 The observed published ADC efficacy data and the strong
pipeline of potentially efficacious new agents is suggesting
a very promising path forward
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