Risk Assessment of Humanized Monoclonal Antibodies and Antibody—Drug Conjugate

17 Pages·2015·1 MB·English

by  Hinrichs, Mary Jane

Risk Assessment of Novel
Biopharmaceutical Platforms
Mary Jane Hinrichs, PhD
Types of Novel Biopharmaceutical Platforms
ICHS6(R1) Preclinical Safety
Evaluation of Biotech-
Targeted Antibody
Derived Pharmaceuticals
nanoparticles Drug
Conjugates
• Allows flexible approach that
can be adapted as needed for
new biopharmaceutical
platforms
Fc-mutated
• General principles can be
mAbs
applied to new technologies;
however, individualized
approach required based on
unique properties of each
Bispecifics platform
• Often involves use of safety
methods that have not yet
been standardized; will
continue to evolve with
scientific advances
(Solaro, 2010; Trail, 2013; Chames, 2011; Brien, 2013)
General Principles
Scientific Case-by-Case
Approach
for Safety Assessment
of Novel • Building confidence that the
safety data provides a reasonable
Biopharmaceuticals
assessment of the potential
human safety risks
No
Yes
No
Yes
No
FIH Start Dose
Yes
Bispecific Formats
Bispecific monoclonal
Engineered proteins composed of
antibody
A2
fragments of two different monoclonal A1
antibodies
Unique Properties to
Diabody
be Considered
A1
A2
• Binds to two different
BiTE Molecules
antigens
• Cytokine release
• Immunogenicity
• Half-life
A1 A2
(Chames, 2011; Brien, 2013)
Case Example – MEDI-565 (AMG 211)
Bi-specific T-cell engager (BiTE®*)
Fusion protein consisting of two scFvs
Antigen 1 – CEA (carcinoembryonic antigen)
CD3
• Highly expressed on multiple solid tumors
• Apical expression on normal tissues
Antigen 2 – CD3 CEA
Cytotoxic
• Engagement with CD3 on T cells results in
activity
activation of cytotoxic T cell response
involving release of proteins such as perforin
and granzyme
Unique Aspects to be Considered:
http://updates.clltopics.org/3528-
• MEDI0565 does not cross-react with CD3 in cyno taking-a-bite-out-of-b-cell-cancers
monkeys or other standard tox species
• Potential for cytokine release
*BiTE® is a registered trademark of
Amgen.
Case example courtesy of Patty Ryan
Lack of Relevant Species for Safety Testing
 MEDI-565 does not bind CD3 in standard tox
N
species (i.e. monkeys or rodents)
Anti-human CEA
MEDI-565  Binds human and chimpanzee CD3 similarly
 Chimpanzee is not a suitable tox model
Anti-human CD3
 No non-specific T cell activation observed
C
 CyS111 binds cyno CD3 and human CEA
NN
 CEA expression similar in cyno and human
Cyno
Anti-human CEA
 In vitro potency lower than MEDI-565 human
Surrogate
 Non-specific T cell activation observed in vitro
(cyS111)
Anti-NHP CD3
10-fold greater binding affinity to CD3
CC
 HyS111 binds murine CD3 and human CEA
Mouse NNN  CEA expression similar in huCEA Tg mouse and
Surrogate Anti-human CEA
human
(hyS111)
 In vitro potency greater than MEDI-565
Anti-murine CD3  Non-specific T cell activation observed in vitro
CCC and in vivo
100-fold greater binding affinity to CD3
Use of Minimum Anticipated Biological Effect Level
Therapeutic Unacceptable
MABEL Range Toxicity
100
NOAEL
80

t 60
c
e
f FIH DOSE RANGE
f
E
40
NOEL?
20
0
10 Minimal Effective 100 1000 10000
Dose Dose or exposure
Pharmacological dose-response
Toxicological dose-response
7
Determination of the MABEL
Affinity/theoretical
receptor
occupancy
Single dose PK
study of MEDI-
565 in monkeys
Parameters used
to generate Cytotoxicity
PK/PD Model
In vitro co culture
assays
Cytokine release
Extrapolate MABEL dose from in vitro data
to establish an appropriate first time in
human dose using available monkey PK T cell activation
data.

Most sensitive measure of pharmacological activity
Modeling for FIH Phase I Dose
 Phase I dose regimen projected based on simulated C-t profiles and in
vitro MABEL
1000.0000
100.0000
Predicted efficacious dose trough above EC50.
)
L
m
/
g 10.0000
n
(
n
EC50
o
it 1.0000
a
r
t
n
e
EC20
c 0.1000
n
o
C Starting dose C below EC20.
max

m
0.0100
u
r
e
S
0.0010
0.0001
0.00E+00 5.00E+00 1.00E+01T ime 1.50E+01 2.00E+01
Antibody Drug Conjugates
Antibodies linked via a stable chemical
linker to a highly potent cytotoxic small
molecule
Unique Properties to
be Considered
Cytotoxic drug
• Relevant species
Linker
• On/off target toxicities
• Need to assess safety
of small molecule as
well as conjugate
• Apply principles of
Reference on Nonclinical Safety
ICHS6(R1) and ICHS9
Testing of ADCs
Roberts et al. 2013. Considerations for
the nonclinical safety evaluation of ADCs
for oncology. Regul. Toxicol. Pharmacol.