Clinical relevance of (unwanted drug-induced)

imm

une responsesPresented at the EBF Focus W

orkshop by PD Dr. Arno Kromm

inga

20 September 2018

2

FDA Imm

unogenicity Guidance, 2016

The sponsor should determine the sensitivity of the assay to have confidence

when reporting im

munogenicity rates. Assay sensitivity represents the low

est concentration at w

hich the antibody preparation consistently produces either a positive result or readout equal to the cut point determ

ined for that particular assay.

FDA recomm

ends that screening and confirmatory ADA assays achieve a sensitivity

of at least 100 nanograms per m

illiliter (ng/mL).Although traditionally FDA has

recomm

ended sensitivity of at least 250–500 ng/mL, recent data suggest that

concentrations as low as 100 ng/m

L may be associated w

ith clinical events (Plotkin 2010; Zhou, Hoofring, et al. 2013).

3

ADA characteristics and Characteristics

Concentration and characteristics of the ADA response observed follow

ing weekly

administration of AM

G 317

Higher ADA concentrations and later time

points were associated w

ith lower trough

AMG 317 m

easurements.

Zhou L, HoofringSA et al, AAPSJ, 2013

4

Determination ofADA Sensitivity

Assay RunLinear Fit

Sigmoidal Fit

Asymm

etric Sigm

oidal Fit

Run1OP1

0,9330,922

0,96

0,7610,615

0,615

Run2OP1

1,1261,172

1,212

1,0480,980

0,998

Run1OP2

1,1461,118

1,166

0,9420,756

0,759

Run2OP2

1,0651,069

1,127

0,9970,891

0,938

Mean

1,0020,940

0,972

SD0,125

0,1870,205

Sensitivity: m

ean + (t0.05df*SD) in ng/mL

1,31,4

1,6

LPC1: m

ean + (t0.01df*SD) in ng/mL

1,41,8

2,4

ADA sensitivity as low as low

ng or even sub-ng range be achieved. The question needs to be discussed w

hether or not these high analytical sensitivities are needed or clinically relevant.

5

Induction of Imm

une Responses

Abbas, Lichtman and Pillai, 2016

The induction of imm

une response is cascade of m

ultiple steps and ultimately

leads to highly specific antibodies and T cells.

6

B Cell Activationand Antibody Production

Abbas, Lichtman and Pillai, 2016

The maturation of antibodies results in antibodies w

ith different binding affinities and functionalities.

7

Red: isotypeBlue: cells

Green: various functions Yellow

: epitope recognition

NaturalAntibodies

HolodickNE et al, Front Im

munol, 2017

Natural antibodies are pre-im

mune antibodies

generated in the absence of exogenous antigenic stim

ulation.

Natural antibodies

✓have the ability to exert a protective or regulatory function

✓show

a pre-existing/imm

ediately imm

une responsive.

8

Diverse Roles of Natural IgM

Antibodies

Natural IgM

plays a role in:

✓Direct pathogen neutralization

✓Classical com

plement activation

✓Ag recruitm

ent and priming of

subsequent TI adaptive imm

unity

✓Ab-dependent cell-m

ediated cytotoxicity

✓Apoptotic cell phagocytosis

✓Clearance of DAM

Ps

✓B cell hom

eostasis

Panda S & Ding JL, J Im

munol, 2015

9

(Possible) Roles of Natural IgG &

Natural IgG

Antibodies

Panda S & Ding JL, J Im

munol, 2015

a.Pathogen recognition and clearance, thus controlling inflam

mation by regulating the

production of cytokines

b.Role in Health and Disease:✓

Controlling or exacerbating autoimm

une diseases,

✓Am

eliorating inflamm

ation,

✓Im

mune regulation and hom

eostasis,

✓Developm

ent of safer and more effective

imm

unomodulators.

10

Pre-existingAntibodies

van Schie, Wolbink, Rispens,m

abs, 2015

AntibodiesDirectedTow

ards: ✓

Idiotype(CDR, FR)

✓Isotype

✓Allotype

✓Heterophilic

antibodies

✓Hinge region

✓Carbohydrates

11

Clinical Relevance of anti-PEG Antibodies

GorovitsB et al. , AAPSJ, 2016

12

Prevalenceand

ConsequenceofPre-existing

AB

XueL &

Rup B, AAPSJ, 2013

a.10.8%

of all study subjects had detectable pre-existing Abs across studies.

b.13%

of subjects with post-treatm

ent ADA w

ere positive for pre-existing antibodies.

13%

87%

ADA Elevation fromPositive Baseline

ADA Elevation fromN

egative Baseline

ADA+Subjects from

Studies Associated with Pre-existing Abs

PercentageN

umberof

Subjects

In all studysubjects

10.8%(103/950)

In healthy volunteers3.6%

(3/84)

In all disease populations11.5%

(100/866)

In disease populations excluding RA

8.5%(38/446)

InRA patients

14.8%(62/420)

13

Anti-CCP AB Detection Prior to the Disease Onset

Rantapää-DahlqvistS et al. , 2003

Sens(%)

Spec (%)

PPV(%

) N

PV (%)

RAPatients

3498

8286

>1.5 years before sym

ptoms

2598

8084

<1.5 years before sym

ptoms

5298

8589

Early RA70

9891

93

14

PredictiveAntibodiesAgainstCCP (in RA)

Accumulated percentage positive sam

ples analyzed before onset of sym

ptoms and at diagnosis.

Kokkonenet al. Arthritis Research &

Therapy 2011

Antibody levels, aspercentage of cut-off valuesbefore and at disease onset

15

Time Course

ofClinical RA Onset

Taylor P et al. Autoimm

une Dis, 2011

Anti-CCP antibodies in the serum

of patients are present as many

as 12 to 14 years prior to the developm

ent of RA. In these studies, 34%

–40% of the RA

patients had anti-CCP+ results prior to disease onset

16

Conclusion

✓Im

mune responses against self or foreign m

ay lead to the formation of detectable antibodies.

✓It is unclear w

hether pre-existing Abs may increase the risk for drug-induced ADA.

✓Antibody form

ation often precedes the clinical onset of imm

une-mediated diseases.

✓Antibody assays cannot be too sensitive.

✓A careful and thorough data interpretation is needed w

hich takes into account the clinical m

anifestation and clinical relevant biomarkers (including PK).

✓The kinetics and type of antibody responses should be m

onitored to assess the risk of developing a treatm

ent-emergent im

mune responses.

✓Post-approval ADA and drug patient m

onitoring should be mandatory.

17

Outlook

–R. Chandler, 1940

“A p

roo

f is alw

ays a

relative th

ing

. It’s an

o

verwh

elmin

g b

ala

nce o

f pro

ba

bilities.”