characterization of antibody drug conjugates by liquid ... · characterization of antibody drug...

Characterization of Antibody Drug Conjugates

by Liquid Chromatography Mass Spectrometry

Olga Friese1, Jacquelynn Smith1, Paul Brown1, James Carroll1, and Jason Rouse2

Mass Spectrometry and Biophysical Characterization (MSBC)

Pfizer Biotherapeutics PharmSci 1St. Louis, MO and 2Andover, MA

3 November 2014

Overview

2

Introduction of ADCs

Structure and Role

Complexities of ADC Construction

Heightened Characterization of ADCs

Top-down Strategy

Intact Mass Analysis and Challenges

Subunit Domain Analysis and Challenges

Peptide Mapping: Reduced and Non-reduced

Summary

Antibody Drug Conjugates (“ADCs”) Come of Age

3

In past 5 years, more IND

submissions for ADCs than in the

previous 15 years

“Naked” antibodies against only 8

distinct tumor targets currently

marketed → mechanism of action

insufficient (ADCC & CDC)

Cytotoxic payload of ADCs

producing compelling efficacy data

(Mylotarg, Adcetris™ & Kadcyla)

0

5

10

15

20

25

30

1993-97 1998-02 2003-07 2008-12

Goals

Improve efficacy

Improve selectivity

Decrease toxicity

Improve therapeutic index

Shapiro, M.A. et al. American Laboratory. August 27, 2012.

Key Components of ADC: An Intricate Morphology

4

Antibody

Highly selective recognition

Targets antigen found only

on target cells

Minimal non-specific

binding

Drug

Highly potent

Non-immunogenic

Dormant during circulation in

blood

Validated mechanism of

action (microtubule inhibition,

DNA damage)

Linker

Not altering mAb characteristics

Stable in plasma

Labile upon internalization to

release drug

Target

Selective expression in

disease

Abundant expression

Internalization upon binding

ADC

5

Cysteine conjugation Lysine conjugation

Bioconjugation Chemistries: Different Level of ADC

Complexity

Site-specific conjugation

Advantages of site specific conjugation Controlled drug loading, eliminate mixtures

Improvement in pharmaceutical properties

– Pharmacokinetics

– Safety

– Stability

Simplify analytics and development

Junutula, J. R et al, Nat Biotechnol, 2008, 26, 925-932

Strop, P, et al Chem Biol, 2013, 20, 161-167

•25/22 Lys in IgG1/IgG4 constant regions

•8 Lys in κ constant region

•4 IgG1 interchain disulfide bonds

•8 potential Cys conjugation sites

Intact Mass

Peptide Mapping

SEC/UV/MS

Subunit Mapping

Reduction

- or - IdeS digestion

UHPLC/UV/MS

Lys-C proteolysis

RP-HPLC/UV/MS

Intact mass: untreated and de-N-glycosylated

Confirmation of sequence fidelity and extent of conjugation via average

mass measurement of intact and de-N-glycosylated molecule

Two-part subunit domain assay using reduction

Confirmation of integrity and extent of conjugation via average mass

measurements of LC and HC domains (triple mutants, conjugation near

IdeS cleavage site)

Three-part subunit domain assay using IdeS enzyme

Confirmation of integrity and extent of conjugation at anticipated and

unanticipated sites via monoisotopic mass measurements of scFc, LC, and

Fd’ subunit domains

Proteolytic mapping using enzymatic digestion

Confirmation of sequence coverage, PTM, and drug site occupancy via

reduced/alkylated peptide mapping;

Confirmation of disulfide connectivity via non-reduced peptide mapping

(cysteine chemistry specific);

Complexity of Mixture, Resolution of Modifications

High

Low

6

Top-down Characterization Strategy for ADC by Mass

Spectrometry

Heightened characterization data is needed for:

• Reference material characterization (IND filing);

• Large scale process development;

• Lot-to-lot comparability.

7

Intact mass analysis is used to confirm:

• Intended ADC primary structure with anticipated conjugation

•Characterization of bulk material

•Drug to antibody ratio (DAR) determination •May or may not be accurate with LC/MS – ionization efficiency might be

impacted by number of drugs

•Drug loading distribution - fraction of antibodies containing zero, one,

two,…, n drugs •May or may not be accurate with LC/MS – ionization efficiency might be

impacted by number of drugs

•Drug distribution of ADC by HIC •Characterization of fractionated material

Intact Mass

SEC/UV/MS

Role of Intact Mass Analysis in Characterization

of ADC

Challenges in LC/MS Analysis of ADC: Compromise

between Large and Small Molecule Analysis

8

LC/MS technology

for Small Molecules

(linker payloads)

• High LC column temperature

• High cone voltage

• High ion source temperature

• Ambient column temperature

• Low cone voltage

• Low ion source temperature

http://www.atlantahostingtalk.com/wp-content/uploads/2014/07/bridging-the-gap.jpg

Challenges Encountered During Intact Mass

Analysis of ADC Using mAb LC/MS Methods

• ADCs (Calicheamicin based ADCs) with acid labile linker payloads

are unstable in the presence of strong acid modifiers (TFA) in mobile

phases;

– Utilized 0.1% formic acid in water as mobile phase A and no acid in ACN

• ADCs with partially reduced disulfides (Cys-based ADCs) do not

remain intact under denaturing conditions of oSEC/MS analysis:

– Utilized native (non-denaturing) SEC/MS using ammonium acetate as a

mobile phase;

– Increased in-source pressure and collision cell voltage for collisional

stabilization (cooling) of the ions

• ADCs with surface exposed linker payloads (site-specific ADCs) are

susceptible to in-source fragmentation under ESI conditions (high

cone voltages and/or source temperatures):

– Utilized lower cone voltages

9

10

AcBut Linker DMH Linker

Structure of ADC with Acid Labile Linker

Acid labile linker poses a challenge to many analytical techniques

Acid labile

Calicheamicin

mass146000 148000 150000 152000 154000 156000 158000

%

0

100

%

0

100150359.4

150558.0

154747.5

154546.0

153081.5

156412.0

11

Mass Spectrum of Intact ADC with Acid Labile Linker:

Impact of Mobile Phase pH (+/-TFA)

+2 Linker

G0F/G0F

+3 Linker

G0F/ G0F

+4 Linker

G0F/G0F

+5 Linker

G0F/ G0F

+3 Calich

G0F/ G0F

+2 Calich

G0F/ G0F

+4 Calich

G0F/ G0F

+5 Calich

G0F/ G0F

• In the presence of strong acid (TFA)

acid labile linker in calicheamicin

payload is cleaved leaving only a 204

Da linker + 0.1%TFA

+ 0.1% FA

• In the absence of strong acid (TFA)

acid labile linker in calicheamicin

payload is not cleaved leaving intact

calicheamicin attached to the mAb

Partial reduction followed by conjugation leads

to multiple ADC isoforms, in some case no

interchain disulfide bonds

(Examples of potential ADC isoforms)

Partial Reduction

Conjugation

Sun, et al., Bioconjugate Chem. 2005, 16, 1282-1290

Possible Structures of ADC with Conventional Cysteine

Conjugation Chemistry

L1 + HHL1

2*HL2 2*L1 + HH2 L1 + HHL3 L1 + HHL3

mAb2 mAb2

2*L1 + HH4 2*L1 + HH4 L1 + H3 + HL2

2*L1 + 2*H3

12

GC3 ADC

mass60000 80000 100000 120000 140000

%

0

10075977.0

53370.0

51547.0 53526.0

75838.0

76134.0

103093.076280.0

103241.0 125693.0

HL + 2drugs

H+1drug

HHL+1drug

HH+2drugs

Zero-charged Deconvoluted Mass Spectra of Cys-

Conjugated ADC under Denaturing oSEC/MS

L+1drug

H+3drugs

GC3 ADC

mass24000 24200 24400 24600 24800 25000

%

0

10024431.0

UV 214nm

Mass Spectra

Mobile Phase

0.1% TFA, 40% AcN

Under denaturing conditions

of LC/MS only covalent

subunits of ADC are observed

mass145000 146000 147000 148000 149000 150000 151000 152000 153000

%

0

100149030.6

147204.6

145378.2

150855.0

149188.0152673.2

mass148000 149000 150000 151000 152000 153000 154000 155000 156000

%

0

100151929.8

150103.8

148271.6

150264.6151791.0

152088.8

153754.4

152242.4153912.2

155578.6154064.2

Intact

Intact

(+2 L/P)

G0F/G0F

G0F/G1F

(+0 L/P)

(+4 L/P)

(+6 L/P)

(+8 L/P)

G1F/G1F

G1F/G1F

G0F/G1F

G0F/G0F

G0F/G0F

G0F/G0F

G0F/G0F

14

UV 214nm Mobile Phase

Ammonium acetate pH 7.0

No acid;

No organic;

de-N-glycosylated

(+2 L/P)

(+0 L/P)

(+4 L/P)

(+6 L/P)

(+8 L/P)

Zero-charged Deconvoluted Mass Spectra of Cys-

Conjugated ADC under Native SEC/MS

Intact ADC molecule with 0, 2, 4, 6,

and 8 L/P is observed under non-

denaturing SEC/MS conditions

Structure of ADC with the Heavy Chain C-terminal

Conjugation Site

15

O

NH

H3N

O

NH2

+

+

specific acyl donor

glutamine tag (LLQGA)

“nonspecific” acyl acceptor

payload

ADC

TG

AGQLL LLQGA

Transglutaminase

AGQLL LLQGA

mAb ADC

Transglutaminase (TG) from

Streptoverticillium mobaraense catalyzes the

formation of covalent bond between glutamine

side chain and a primary amine

Surface accessible glutamine tag LLQGA at

the C-terminus of the heavy chain results in 2

drugs conjugated to the mAb

Strop, P, et al Chem Biol, 2013, 20, 161-167

16

Xevo QTOF

CV 40V

CV 30V

Optimization of ESI source parameters to

reduced in-source fragmentation:

cone voltage;

source temperature;

source pressure (backing pressure);

flow rate *

*

* In-source fragmentation is the most sensitive

to cone voltages;

In-source fragmentation is reduced by

lowering cone voltage, adduct formation is

increased;

mAb(2)

Mass Spectra of ADC with the Surface Exposed Linker

Payload (TG Chemistry): In-source Fragmentations

* in source fragmentation

17

Subunit domain analysis is used to confirm: • Intended ADC primary structure with anticipated conjugation

•Quick and reliable “sequence” verification via accurate mass with 100% coverage

•Localize major/minor/trace modifications to subunits/domains;

•Rapid scFc N-glycan profiling

Role of Subunit Domain Analysis in

Characterization of ADC

30 min

37 °C

pH 6.6

Guanidine

DTT

90 min

37 °C

www.genovis.com/

18 18

Notch 3 DSI Ref Material _2050.d

0

100

200

300

400

Intens.

[mAU]

20 25 30 35 40 45 50 Time [min]

Notch 3 DS 70676-121_2048.d

50

100

150

200

250

Intens.

[mAU]

20 25 30 35 40 45 50 Time [min]

scFc(0)

LC(0)

LC(1)

Fd’(1)

Fd’(0)

Fd’(2b)

Fd’(3)

scFc agly

Fd’(1)-water

Fd’(2a)

scFc(0)

scFc agly

scFc Ox

LC(0) Fd’(0)

IdeS

Fd’ Ox

Fd’ -water

Fd’(2c)

scFc Ox IdeS

Ides Enzyme

-S-S - Reduction

ADC

mAb

UV215nm Profiles

•100% sequence coverage for mAb and ADC

•Complete, definitive assessment of intended ADC covalent structure (integrity)

•Quantitative assessment of the extent of conjugation for each subunit/domain

Number in ( ) indicates number

of drugs attached

Hinge Region Sequences of IgGs

Three-Part Subunit Domain Mapping of Cysteine-Conjugated

ADC: Confirmation of Conjugation at Intended Sites

Mass Spectra of scFc and LC in Three-Part Subunit

Domain Mapping of Cysteine Conjugated ADC

19

'24992.348

1+

'25220.463

1+

'25382.530

1+

'25544.571

1+

+MS, 13.5-14.3min, 100%=2427, Deconvoluted (MaxEnt)

0.0

0.5

1.0

1.5

4x10

Intens.

24800 25000 25200 25400 25600 25800 26000 m/z

'23425.494

1+Notch-3 ADC Reduced CN_1356.d: +MS, 7.7-8.1min, 100%=1874, Deconvoluted (MaxEnt)

'24766.244

1+Notch-3 ADC Reduced CN_1356.d: +MS, 10.4-10.9min, 100%=1171, Deconvoluted (MaxEnt)

0

200

400

600

800

1000

Intens.

[%]

0

100

200

300

400

[%]

23000 23500 24000 24500 25000 25500 26000 m/z

scFc

LC(0)

LC(1)

G1F

Man5 G2F + NeuAc

1341 Da

G0F

G2F

LC with one drug conjugated

This is expected since this

subunit contains 1 interchain Cys

scFC with no drug conjugated

This is expected since this

subunit does not contain any

interchain Cys

LC

Mass Spectra of Fd’ in Three-Part Subunit Mapping

of Cysteine Conjugated ADC

20

'24965.435

1+Notch-3 ADC 3-part_1359.d: +MS, 26.8-27.7min, 100%=724, Deconvoluted (MaxEnt)

'26306.168


'26861.457

1+

'27646.881


'28987.632


0

200

400

Intens.

[%]

0

200

400

600

800

[%]

0

50

100

150

200

[%]

0

20

40

60

80

[%]

25000 26000 27000 28000 29000 m/z

Fd’(0)

Fd’(1)

Fd’(2)

Fd’(3)

1341 Da

1341 Da

1341 Da

Fd’ with one, two and three drugs conjugated

This is expected since this subunit contains 3 interchain Cys

21

Trop 2 ADC RN927 100mm_1877.d

0

100

200

300

400

500

Intens.

[mAU]

22 24 26 28 30 32 34 36 38 Time [min]

Trop2 TS1 ADC_1646.d: Base Peak UV Chromatogram, 215 nm

Trop2 RN927 DS 7mgml_2392.d: Base Peak UV Chromatogram, 215 nm

0

100

200

300

400

500

Intens.

[mAU]

0

100

200

300

400

500

Intens.

[mAU]

10 15 20 25 30 Time [min]

Trop2 TS1 ADC_1646.d: Base Peak UV Chromatogram, 215 nm

Trop2 RN927 DS 7mgml_2392.d: Base Peak UV Chromatogram, 215 nm

0

100

200

300

400

500

Intens.

[mAU]

0

100

200

300

400

500

Intens.

[mAU]

10 15 20 25 30 Time [min]

Waters C4

BEH Column

Agilent C3

Column

Separation Method

Technology C2

(MEB2) Column

scFc(1) LC(0)

Fd’(0)

scFc(1) LC(0)

Fd’(0)

scFc(1) LC(0)

Fd’(0)

Challenges Encountered During RP-HPLC/MS Analysis of

ADCs with Highly Hydrophobic Subunits

• Fd’ domain did not elute from C4

column due to its hydrophobic

nature

• C3 column separation resulted

in a partial elution of Fd’ domain

• Low carbon content C2 column

resulted in a complete elution of

Fd’ domain, however peak shape

is broad and shelf life of column is

very short

Note: separation conditions are different between experiments

22

SCRx4 Red DSI 128926-26_2023.d

SCRx4 Red DS 00706209-0062_2027.d0

250

500

750

1000

Intens.

[mAU]

0

100

200

300

400

500

600

[mAU]

10 15 20 25 30 35 40 Time [min]

mAb

HC

(D

/P 1

…2

74

)

HC

(D/P

27

4…

44

9)

LC

Ox, D

ea

mid

ati

on

LC

HC

LC ADC

N-acetyl epsilon calicheamicin

LC

Ox

LC

+ 1

Lin

ker

LC

+ 1

Lin

ker HC

+ 1

Lin

ker

HC

+ 2

Lin

ker

HC

+ 3

Lin

ker

HC

+ 3

Lin

ker

HC

+ 4

Lin

ker

HC

+ 2

Lin

ker

HC

+ 3

Lin

ker

HC

+ 3

Lin

ker

-S-S- Reduction

HC + linker(s)

Two-Part Subunit Mapping of Lysine-Conjugated ADC:

Confirmation of Conjugation at Intended Sites

• Three-part subunit domain data is very complex;

• IdeS digestion is incomplete due to the nearby conjugation at

the IdeS cleavage site;

• Two-part subunit assay is preferred. It provides good

resolution of HC with various number of linkers

23

RT: 5.00 - 166.00

10 20 30 40 50 60 70 80

Time (min)

0

100000

200000

300000

0

100000

200000

300000

uA

U

NL:7.51E5

nm=213.5-214.5 PDA 20130408OVF05

NL:6.74E5

nm=213.5-214.5 PDA 20130408ovf06

90 100 110 120 130 140 150 160

Time (min)

0

200000

400000

600000

uA

U

0

200000

400000

600000

uA

U

NL:7.51E5

nm=213.5-214.5 PDA 20130408OVF05

NL:6.74E5

nm=213.5-214.5 PDA 20130408ovf06

LK1

5+1

dru

g

HK

13

HK

14

HK

13

HK

14

+1

dru

g H

K1

3H

K1

4+

1d

rug

HK

13

HK

14

+2

dru

gs

HK

12

+1

dru

g1

HK

19

HK

23

LK

12

H

K1

0H

K1

1,

HK

11

LK6

LK

15

HK

29

LK9

LK1

0

HK

3, H

k31

P

am

HK

31

H

K2

2

LK1

4

HK

24

HK

25

, H

K2

5

HK

6

LK1

^

HK

26

LK

11

, H

K5

LK

1

LK2

H

K1

6

HK

30

, H

K3

1 C

-te

rm e

xt

HK

27

H

K2

7#

HK

27

#

HK

15

, H

K2

8

LK7

HK

15

ox

HK

1^ LK

8

HK

1

HK

17

HK

18

G

0F

HK

2

HK

4

LK5

HK

7H

K8

HK

30

# H

K9

, LK

4,

HK

21

* * LK5

succ

HK

13

HK

12

HK12(1)

LK15(1)

HK13HK14(1,0 or 0,1 or 2)

Reduced and Alkylated Lys-C Mapping of ADC: Monitoring

Sites of Conjugation

•All linker payload-conjugated

species are as expected;

•They correspond to addition of

linker payload to Cys involved in

the interchain disulfide bonds;

•No unexpected linker payload

conjugation sites are observed;

•Due to hydrophobic nature of

linker payload they elute late in

the peptide map

mAb

mAb

ADC

ADC

0-85 min

85-165 min

24

pH 8.2

pH 7.5

RT: 129.66 - 157.69

130 135 140 145 150 155

Time (min)

65

70

75

80

85

90

95

100

Relat

ive A

bsor

banc

e

NL:

1.59E5

Channel A

UV

20130402O

VFJNS02_

130402192

058

NL:

1.82E5

Channel A

UV

20130408o

vf06

4000 4050 4100 4150 4200 4250 4300

m/z

0

50

100

0

50

100

Re

lative

Ab

un

da

nce

4146.1455

4128.1428

NL: 4.01E4

20130408ovf06_xtract#285

4 RT: 145.87 AV: 1 T:

FTMS + p ESI Full ms

[247.00-8003.00]

NL: 5.85E5

20130408ovf06_xtract#289

6 RT: 148.00 AV: 1 T:

FTMS + p ESI Full ms

[247.00-5022.43]

N

O

O

S Payload

HN

O

SPayload

CO2H

+H2O

Maleimide conjugated ADCs

undergo hydrolysis at high pH

HK13HK14 + 1 drug

HK13HK14 + 18 Da+ 1 drug

HK13HK14 + 1 drug

R/A Lys-C Mapping of Cysteine Conjugated ADC at High pH

Leads to Hydrolysis of Linker Payload

HK13HK14 + 18Da

+1 drug UV Profiles

Mass Spectra

pH optimal for enzymatic digestions of

mAbs are not always suitable for ADCs,

especially for those with hydrolysable

linker payload

130-155 min

Characterization Strategy of Alkylated Non-Reduced

Peptide Maps of Cysteine-Conjugated ADC

• Alkylate Cys to prevent SH mispairing during proteolytic digestion;

• Look for expected disulfide linked peptides predicted for IgG1 connectivity;

• Look for interchain cysteine-containing peptides with drug payload attachment;

• Look for potential mispaired peptides for interchain cysteine-containing peptides with drug;

• Look for levels of free cysteines at every cysteine-containing peptide – mass shifted due to

alkylation;

25

LT2-ss-LT7

LT11-ss-LT18

HT2-ss-HT10

HT14-ss-HT15

HT20-(2x)ss-HT20*

HT22-ss-HT28

HT36-ss-HT41

Light Chain

Hinge region

Intrachain Disulfide

Linked Peptides

Interchain Disulfide

Linked Peptides

LT20-ss-HT19*

IgG1 ADC

Disulfide Linked Peptides in Non-Reduced Tryptic

Map of Cysteine Conjugated ADC

*Observed only if partially reduced

LT20-drug

HT19-drug

HT20-drug

HT20-2xdrugs

HT20-drug-ss-

HT20-drug*

HT20-drug-ss-

HT20

26

trypsin

or Heavy Chain

RT: 28.9 - 129.9

30 40 50 60 70 80 90 100 110 120

Time (min)

0

10

20

30

40

50

60

70

80

90

100

Re

lativ

e A

bu

nd

an

ce

0

10

20

30

40

50

60

70

80

90

100

Re

lativ

e A

bu

nd

an

ce

53.1

69.5

62.9

77.8

88.0

88.654.5

89.794.1

124.4

4.5x106

1.5x106

LT2-ss-LT7

LT11-ss-LT18

HT2-ss-HT10

HT14-ss-HT15

HT20-(2x)ss-HT20

HT22-ss-HT28

HT36-ss-HT41

LT20-drug HT19-drug

HT20-2xdrug

• All interchain disulfide-linked peptides

observed except LT20-ss-HT19;

• No HT20-drug is observed;

• No HT20-drug-ss-HT20 is observed;

• No HT20-drug-ss-HT20-drug is observed:

Non-Reduced Peptide Mapping of Cysteine-Conjugated ADC:

EMC for Disulfide and Drug Linked Peptides

LT - light chain tryptic peptide

HT - heavy chain tryptic peptide

27

Disulfide-linked peptides

Drug-conjugated peptides

28

RT: 9.8 - 119.4

20 40 60 80 100

Time (min)

0

20

40

60

80

100

Re

lative

Ab

un

da

nce

0

20

40

60

80

100

Re

lative

Ab

un

da

nce

0

20

40

60

80

100

Re

lative

Ab

un

da

nce

103.9

100.8

97.8

74.6

45.8

29.4

50.2

51.1

37.7

54.059.5

89.0

6x104

HT20-drug-ss-HT19

HT20-drug-ss-LT20

Mispaired hinge region

HT20-drug peptide

~ 4% by ion intensities

HT20-drug-ss-HT19 HT20-drug-ss-LT20

Non-Reduced Peptide Mapping of Cysteine Conjugated ADC:

EMC for Mispaired Peptides

Heightened Characterization of ADCs by MS is

Driven by Conjugation Chemistry

29

Methods Conventional Chemistry Site-Specific Chemistry

Lysine Cysteine Glutamine Cysteine

Native SEC/MS

Organic SEC/MS

Two-Part Subunit

Domain Mapping (LC

and HC)

Three-Part Subunit

Domain Mapping

(scFc, LC, and Fd’)

Reduced/Alkylated

Peptide Mapping

Non-

Reduced/Alkylated

Peptide Mapping

- Only if linker payload is acid sensitive

Summary

Mass Spectrometry is a powerful tool for heightened characterization of

ADCs

A tiered “top-down” analysis approach utilizing the latest

technologies (UHR MS) can provide rapid, definitive product quality

information at each stage of development

Intact mass - Confirms sequence fidelity and extent of conjugation

Subunit domain assay - Confirms integrity and extent of conjugation at the scFc, LC,

and Fd’ subunit domain level

Proteolytic mapping using enzymatic digestion - Confirms sequence coverage,

PTM, and drug site occupancy at the peptide level

Improvements in productivity of ADC’s characterization can be realized

when several new technologies merge

IdeS or other proteolytic enzymes, UHPLC, and UHR MS have revolutionized

ADCs characterization, and coming next is automated data analysis with report

generation

30

Acknowledgement

• Projects Team members

Jeff Borgmeyer - analytical leader

Heyi Li – analytical leader

Jason Starkey – analytical leader

Qingping(Jim) Jiang

Lawrence Chen

Debra Meyer

Scott Sprague

Bill Romanow

Jennyfer Smith

Libbey Yates

Tom Schomogy

Margaret Ruesch – VP of ARD

Steve Max – project leader

31

• Mass Spectrometry group

members

Jacquelynn Smith

Paul Brown

Justin Sperry

Kathleen Cornelius

Matthew Thompson

James Carroll – group leader

Jason Rouse – Sr. director

• Oncology RU project team

members

• Rinat team members

characterization of antibody drug conjugates by liquid ... · characterization of antibody drug...

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