�ABL lmmunobiology CASE STUDY ADVANCED BIOSCIENCE LABORATORIES

CLINICAL CHARACTERIZATION OF THE PD PROFILE OF A MONOCLONAL ANTIBODY

We invite you to discover our expertise through a series of real case studies :

► IMMUNOPHENOTYPING

WHAT DO ALL CANDIDATE IMMUNOTHERAPIES HAVE IN COMMON? Whether in the preclinical or clinical stage, all immunotherapies need robust and reliable monitoring tools to characterize and track the immune response. Our expertise lies in the monitoring of the immune response within a regulatory compliant setting. We have supported hundreds of preclinical and clinical studies evaluating the safety and efficacy of candidate Monoclonal Antibodies (MAbs), Antibody Drug Conjugates (ADCs), therapeutic vaccines, Chimeric Antigen Receptor T cells (CAR-T cells) and several other novel immunotherapies.

► FUNCTIONAL ASSAYS

► SOLUBLE BIOMARKERS

► DRUG-TARGET INTERACTIONS

INTRODUCTION One of the major challenges encountered during the preclinical and clinical development of a new drug is the characterization of its pharmacokinetic (PK) and pharmacodynamie (PD) properties. Preclinical PK/PD data issued from either in vitro or ex vivo animal studies, provide the basis for in silico modeling and simulation of the human PK/PD characteristics of the drug in humans, leading to determination of the minimum anticipated biological effect level (MABEL) and the selection of the first human dose for clinical trials. Clinical PK/PD data from early phase clinical trials are highly valued in that they confirm or update current PK and PD models in addition to optimizing dosing regimens for subsequent efficacy and safety studies and later-stage clinical trials. Ligand binding assays are designed to quantify the binding of therapeutics to their targets, either by ELISA-based assays for circulating targets or by receptor occupancy assays for those

located on the cell surface. When combined with the PK profile, the resulting data can establish PK/PD relationships and trends, which are essential for guiding dose decisions.

ASSESSMENT OF DRUG-TARGET INTERACTIONS Confirmation and evaluation of the binding of a biotherapeutic to its cellular target is mandatory in the early development phases as it helps to define the PD profile of that drug. To address those needs, we conduct several flow cytometry-based receptor occupancy (RO) assays to quantitatively assess the binding of a therapeutic agent to its target. To ensure that reliable and high quality results are generated from these RO assays, careful assay design and qualification, characterization of key reagents, data normalization and thorough planning for study implementation are of critical importance. For more information on our ligand binding offerings, please contact us at : info@active-biomarkers.com.

CASE STUDY

FUNCTIONAL ASSAYS

SOLUBLE BIOMARKERS

DRUG-TARGET INTERACTIONS

IMMUNOPHENOTYPING

PHASE OVERALL OBJECTIVES QUESTIONS TASKS

Preclinical phases Demonstration of biological activity in experimental animal models

What are the efficacy and safety profilesof the new drug in animal models? Understand the mechanism of action

Accrual of toxicology data to supportinitial dosing in humans

What dose range should be studied in early clinical trials ?

Demonstration of biologic activity in experimental animal models

Identify lead candidate Predict human clearance based on in vivo/in vitro data

Predict efficacy estimates

Integrate clearance, potency, and bioavailability estimates for dose projections

Phase I Assess tolerable dose limits What is the maximum tolerable dose? Develop or update the PK and PD models

Assess PK and PD characteristics What are the PK and PD attributes in initial human studies?

Simulate exposure and response for intended dosing regimens

Quantifiy the variability in PK and PD

Phase IIA Demonstrate efficacy in the intended population, per indication

What are the attributes of the drug intarget population compared to the standard of care ?

Develop a drug-disease model to understand time course of disease progres-sion and dose-response to interventions

Phase IIB Optimal use in target population, per indication

What trial design for a PoC/Phase IIB study willdemonstrate efficacy in the target population

Simulate outcome given assumptionsand study design considerations

Establish dose to be evaluated inphase III

What are the critical aspects reflecting thevalue of a PoC study vs. larger phase II study(i.e. study duration, optimal sample collectionschedules, biomarkers and endpoints…)?

Use simulations or optimization tools to design dosing and sampling schemes

Analyse dose-exposure-response data

Stress test and validate the populationPK/PD model

Assess efficacy/toxicity profiles of thenew drug relative to standard of care

Phase III Demonstrate safety and efficacy for clinical use

Do the intented dose(s) demonstrate the desired safety and efficacy in the population ? Validate the population PK/PD model

Establish/confirm dose-exposure-responserelationship in target populations

Is the dose likely to change in a special population ?

Assess need for dose adjustment in special populations

Platine’s offer

Platine Pharma Services provides its customers with expert advices for the most adapted assays to detect and quantify exogenousmolecules, then performs optimization and validation before sample testing.Based on its qualified flow cytometry, ELISA, Luminex® and Mesoscale Discovery® platforms, Platine Pharma Services offersstate-of-the-art assays to test preclinical or clinical samples.

For more information on our services, please contact us at info@platine-lab.com.

Case study

In the context of a phase II clinical trial evaluating a new therapeutic antibody targeting lymphocyte subsets, a criticalquestion was to characterize the pharmacodynamic behaviorof this investigational drug (i.e. the saturation level of its target on lymphocyte subsets. See figure 1) in two differentregimens of dosing. Platine Pharma Services was asked tooptimize and perform a pre-study validation of an assay enabling the measurement of the cell surface level of saturation of receptors targeted by this new therapeutic antibody, and to monitor this level of saturation on lymphocyte subsets in patient blood samples collected allalong the clinical trial.

We have then developed and optimized a flow cytometryligand binding assay, based on the detection, directly inthe patient whole blood, of the drug bound to its cellulartargets using a monoclonal antibody directed against thedrug (See figure 2). Validation was then performed according to regulatory guidelines and/or whitepaper [5, 6].This assay was shown to be suitable to assess the level ofreceptor saturation by the drug.

TABLE 1: Application of PK/PD data during drug development stages (adapted from Chien et al. [2]).

FIGURE 1: Example of the evolution of the saturation level

of cell surface receptors targeted by a therapeutic antibody before and after dosing.

FIGURE 2: 4 color flow cytometric based receptor saturation assay.

Patient whole blood was washed to discard free drug, then stainedwith anti-CD45, anti-CDX, anti-CDY and secondary antibody specific of

the drug. Red blood cells were then lysed before sample acquisition ona BD canto II flow cytometer. Lymphocytes were defined on the basis

of CD45 expression and SSC level (upper left hand quadrant). Lymphocyte subset 1 and 2 were defined as CDX-CDY+ and CDX+CDY-/+

respectively (upper right hand quadrant). Fluorescent intensity of antibody directed against the drug was then analyzed on both

lymphocyte subsets; revealing cells that express receptors bound to the drug and their level of saturation.

SAMPLETIMEPOINT

Predose

24 h post-dose

1 week post-dose

2 weeks post-dose

3 weeks post-dose

CELL SATURATIONSCHEME

0%

100%

60%

20%

0%

THEORETICALSATURATION

LEVEL

FLOW CYTOMETRIC

ANALYSIS

Targeted cellsurface receptors

Therapeutic antibody

Ungated Gated on lymphocytes

Gated on subset 1 Gated on subset 2

CD45 CDX

Anti-drug

Cells expressing receptorssaturated by the drug

Anti-drug

SSC

CDY

Coun

t

Coun

t

Lymphocytes

Subset 1

Subset 2

Exe-Fiches A3-2 volets Platine:Mise en page 1 21/05/12 20:13 Page2

PHASE OVERALL OBJECTIVES QUESTIONS TASKS

Preclinical phases Demonstration of biological activity in experimental animal models

What are the efficacy and safety profilesof the new drug in animal models? Understand the mechanism of action

Accrual of toxicology data to supportinitial dosing in humans

What dose range should be studied in early clinical trials ?

Demonstration of biologic activity in experimental animal models

Identify lead candidate Predict human clearance based on in vivo/in vitro data

Predict efficacy estimates

Integrate clearance, potency, and bioavailability estimates for dose projections

Phase I Assess tolerable dose limits What is the maximum tolerable dose? Develop or update the PK and PD models

Assess PK and PD characteristics What are the PK and PD attributes in initial human studies?

Simulate exposure and response for intended dosing regimens

Quantifiy the variability in PK and PD

Phase IIA Demonstrate efficacy in the intended population, per indication

What are the attributes of the drug intarget population compared to the standard of care ?

Develop a drug-disease model to understand time course of disease progres-sion and dose-response to interventions

Phase IIB Optimal use in target population, per indication

What trial design for a PoC/Phase IIB study willdemonstrate efficacy in the target population

Simulate outcome given assumptionsand study design considerations

Establish dose to be evaluated inphase III

What are the critical aspects reflecting thevalue of a PoC study vs. larger phase II study(i.e. study duration, optimal sample collectionschedules, biomarkers and endpoints…)?

Use simulations or optimization tools to design dosing and sampling schemes

Analyse dose-exposure-response data

Stress test and validate the populationPK/PD model

Assess efficacy/toxicity profiles of thenew drug relative to standard of care

Phase III Demonstrate safety and efficacy for clinical use

Do the intented dose(s) demonstrate the desired safety and efficacy in the population ? Validate the population PK/PD model

Establish/confirm dose-exposure-responserelationship in target populations

Is the dose likely to change in a special population ?

Assess need for dose adjustment in special populations

Platine’s offer

Platine Pharma Services provides its customers with expert advices for the most adapted assays to detect and quantify exogenousmolecules, then performs optimization and validation before sample testing.Based on its qualified flow cytometry, ELISA, Luminex® and Mesoscale Discovery® platforms, Platine Pharma Services offersstate-of-the-art assays to test preclinical or clinical samples.

For more information on our services, please contact us at info@platine-lab.com.

Case study

In the context of a phase II clinical trial evaluating a new therapeutic antibody targeting lymphocyte subsets, a criticalquestion was to characterize the pharmacodynamic behaviorof this investigational drug (i.e. the saturation level of its target on lymphocyte subsets. See figure 1) in two differentregimens of dosing. Platine Pharma Services was asked tooptimize and perform a pre-study validation of an assay enabling the measurement of the cell surface level of saturation of receptors targeted by this new therapeutic antibody, and to monitor this level of saturation on lymphocyte subsets in patient blood samples collected allalong the clinical trial.

We have then developed and optimized a flow cytometryligand binding assay, based on the detection, directly inthe patient whole blood, of the drug bound to its cellulartargets using a monoclonal antibody directed against thedrug (See figure 2). Validation was then performed according to regulatory guidelines and/or whitepaper [5, 6].This assay was shown to be suitable to assess the level ofreceptor saturation by the drug.

TABLE 1: Application of PK/PD data during drug development stages (adapted from Chien et al. [2]).

FIGURE 1: Example of the evolution of the saturation level

of cell surface receptors targeted by a therapeutic antibody before and after dosing.

FIGURE 2: 4 color flow cytometric based receptor saturation assay.

Patient whole blood was washed to discard free drug, then stainedwith anti-CD45, anti-CDX, anti-CDY and secondary antibody specific of

the drug. Red blood cells were then lysed before sample acquisition ona BD canto II flow cytometer. Lymphocytes were defined on the basis

of CD45 expression and SSC level (upper left hand quadrant). Lymphocyte subset 1 and 2 were defined as CDX-CDY+ and CDX+CDY-/+

respectively (upper right hand quadrant). Fluorescent intensity of antibody directed against the drug was then analyzed on both

lymphocyte subsets; revealing cells that express receptors bound to the drug and their level of saturation.

SAMPLETIMEPOINT

Predose

24 h post-dose

1 week post-dose

2 weeks post-dose

3 weeks post-dose

CELL SATURATIONSCHEME

0%

100%

60%

20%

0%

THEORETICALSATURATION

LEVEL

FLOW CYTOMETRIC

ANALYSIS

Targeted cellsurface receptors

Therapeutic antibody

Ungated Gated on lymphocytes

Gated on subset 1 Gated on subset 2

CD45 CDX

Anti-drug

Cells expressing receptorssaturated by the drug

Anti-drug

SSC

CDY

Coun

t

Coun

t

Lymphocytes

Subset 1

Subset 2

Exe-Fiches A3-2 volets Platine:Mise en page 1 21/05/12 20:13 Page2

PHASE OVERALL OBJECTIVES QUESTIONS TASKS

Preclinical phases Demonstration of biological activity in experimental animal models

What are the efficacy and safety profilesof the new drug in animal models? Understand the mechanism of action

Accrual of toxicology data to supportinitial dosing in humans

What dose range should be studied in early clinical trials ?

Demonstration of biologic activity in experimental animal models

Identify lead candidate Predict human clearance based on in vivo/in vitro data

Predict efficacy estimates

Integrate clearance, potency, and bioavailability estimates for dose projections

Phase I Assess tolerable dose limits What is the maximum tolerable dose? Develop or update the PK and PD models

Assess PK and PD characteristics What are the PK and PD attributes in initial human studies?

Simulate exposure and response for intended dosing regimens

Quantifiy the variability in PK and PD

Phase IIA Demonstrate efficacy in the intended population, per indication

What are the attributes of the drug intarget population compared to the standard of care ?

Develop a drug-disease model to understand time course of disease progres-sion and dose-response to interventions

Phase IIB Optimal use in target population, per indication

What trial design for a PoC/Phase IIB study willdemonstrate efficacy in the target population

Simulate outcome given assumptionsand study design considerations

Establish dose to be evaluated inphase III

What are the critical aspects reflecting thevalue of a PoC study vs. larger phase II study(i.e. study duration, optimal sample collectionschedules, biomarkers and endpoints…)?

Use simulations or optimization tools to design dosing and sampling schemes

Analyse dose-exposure-response data

Stress test and validate the populationPK/PD model

Assess efficacy/toxicity profiles of thenew drug relative to standard of care

Phase III Demonstrate safety and efficacy for clinical use

Do the intented dose(s) demonstrate the desired safety and efficacy in the population ? Validate the population PK/PD model

Establish/confirm dose-exposure-responserelationship in target populations

Is the dose likely to change in a special population ?

Assess need for dose adjustment in special populations

Platine’s offer

Platine Pharma Services provides its customers with expert advices for the most adapted assays to detect and quantify exogenousmolecules, then performs optimization and validation before sample testing.Based on its qualified flow cytometry, ELISA, Luminex® and Mesoscale Discovery® platforms, Platine Pharma Services offersstate-of-the-art assays to test preclinical or clinical samples.

For more information on our services, please contact us at info@platine-lab.com.

Case study

In the context of a phase II clinical trial evaluating a new therapeutic antibody targeting lymphocyte subsets, a criticalquestion was to characterize the pharmacodynamic behaviorof this investigational drug (i.e. the saturation level of its target on lymphocyte subsets. See figure 1) in two differentregimens of dosing. Platine Pharma Services was asked tooptimize and perform a pre-study validation of an assay enabling the measurement of the cell surface level of saturation of receptors targeted by this new therapeutic antibody, and to monitor this level of saturation on lymphocyte subsets in patient blood samples collected allalong the clinical trial.

We have then developed and optimized a flow cytometryligand binding assay, based on the detection, directly inthe patient whole blood, of the drug bound to its cellulartargets using a monoclonal antibody directed against thedrug (See figure 2). Validation was then performed according to regulatory guidelines and/or whitepaper [5, 6].This assay was shown to be suitable to assess the level ofreceptor saturation by the drug.

TABLE 1: Application of PK/PD data during drug development stages (adapted from Chien et al. [2]).

FIGURE 1: Example of the evolution of the saturation level

of cell surface receptors targeted by a therapeutic antibody before and after dosing.

FIGURE 2: 4 color flow cytometric based receptor saturation assay.

Patient whole blood was washed to discard free drug, then stainedwith anti-CD45, anti-CDX, anti-CDY and secondary antibody specific of

the drug. Red blood cells were then lysed before sample acquisition ona BD canto II flow cytometer. Lymphocytes were defined on the basis

of CD45 expression and SSC level (upper left hand quadrant). Lymphocyte subset 1 and 2 were defined as CDX-CDY+ and CDX+CDY-/+

respectively (upper right hand quadrant). Fluorescent intensity of antibody directed against the drug was then analyzed on both

lymphocyte subsets; revealing cells that express receptors bound to the drug and their level of saturation.

SAMPLETIMEPOINT

Predose

24 h post-dose

1 week post-dose

2 weeks post-dose

3 weeks post-dose

CELL SATURATIONSCHEME

0%

100%

60%

20%

0%

THEORETICALSATURATION

LEVEL

FLOW CYTOMETRIC

ANALYSIS

Targeted cellsurface receptors

Therapeutic antibody

Ungated Gated on lymphocytes

Gated on subset 1 Gated on subset 2

CD45 CDX

Anti-drug

Cells expressing receptorssaturated by the drug

Anti-drug

SSC

CDY

Coun

t

Coun

t

Lymphocytes

Subset 1

Subset 2

Exe-Fiches A3-2 volets Platine:Mise en page 1 21/05/12 20:13 Page2

PHASE OVERALL OBJECTIVES QUESTIONS TASKS

Preclinical phases Demonstration of biological activity in experimental animal models

What are the efficacy and safety profilesof the new drug in animal models? Understand the mechanism of action

Accrual of toxicology data to supportinitial dosing in humans

What dose range should be studied in early clinical trials ?

Demonstration of biologic activity in experimental animal models

Identify lead candidate Predict human clearance based on in vivo/in vitro data

Predict efficacy estimates

Integrate clearance, potency, and bioavailability estimates for dose projections

Phase I Assess tolerable dose limits What is the maximum tolerable dose? Develop or update the PK and PD models

Assess PK and PD characteristics What are the PK and PD attributes in initial human studies?

Simulate exposure and response for intended dosing regimens

Quantifiy the variability in PK and PD

Phase IIA Demonstrate efficacy in the intended population, per indication

What are the attributes of the drug intarget population compared to the standard of care ?

Develop a drug-disease model to understand time course of disease progres-sion and dose-response to interventions

Phase IIB Optimal use in target population, per indication

What trial design for a PoC/Phase IIB study willdemonstrate efficacy in the target population

Simulate outcome given assumptionsand study design considerations

Establish dose to be evaluated inphase III

What are the critical aspects reflecting thevalue of a PoC study vs. larger phase II study(i.e. study duration, optimal sample collectionschedules, biomarkers and endpoints…)?

Use simulations or optimization tools to design dosing and sampling schemes

Analyse dose-exposure-response data

Stress test and validate the populationPK/PD model

Assess efficacy/toxicity profiles of thenew drug relative to standard of care

Phase III Demonstrate safety and efficacy for clinical use

Do the intented dose(s) demonstrate the desired safety and efficacy in the population ? Validate the population PK/PD model

Establish/confirm dose-exposure-responserelationship in target populations

Is the dose likely to change in a special population ?

Assess need for dose adjustment in special populations

Platine’s offer

Platine Pharma Services provides its customers with expert advices for the most adapted assays to detect and quantify exogenousmolecules, then performs optimization and validation before sample testing.Based on its qualified flow cytometry, ELISA, Luminex® and Mesoscale Discovery® platforms, Platine Pharma Services offersstate-of-the-art assays to test preclinical or clinical samples.

For more information on our services, please contact us at info@platine-lab.com.

Case study

In the context of a phase II clinical trial evaluating a new therapeutic antibody targeting lymphocyte subsets, a criticalquestion was to characterize the pharmacodynamic behaviorof this investigational drug (i.e. the saturation level of its target on lymphocyte subsets. See figure 1) in two differentregimens of dosing. Platine Pharma Services was asked tooptimize and perform a pre-study validation of an assay enabling the measurement of the cell surface level of saturation of receptors targeted by this new therapeutic antibody, and to monitor this level of saturation on lymphocyte subsets in patient blood samples collected allalong the clinical trial.

We have then developed and optimized a flow cytometryligand binding assay, based on the detection, directly inthe patient whole blood, of the drug bound to its cellulartargets using a monoclonal antibody directed against thedrug (See figure 2). Validation was then performed according to regulatory guidelines and/or whitepaper [5, 6].This assay was shown to be suitable to assess the level ofreceptor saturation by the drug.

TABLE 1: Application of PK/PD data during drug development stages (adapted from Chien et al. [2]).

FIGURE 1: Example of the evolution of the saturation level

of cell surface receptors targeted by a therapeutic antibody before and after dosing.

FIGURE 2: 4 color flow cytometric based receptor saturation assay.

Patient whole blood was washed to discard free drug, then stainedwith anti-CD45, anti-CDX, anti-CDY and secondary antibody specific of

the drug. Red blood cells were then lysed before sample acquisition ona BD canto II flow cytometer. Lymphocytes were defined on the basis

of CD45 expression and SSC level (upper left hand quadrant). Lymphocyte subset 1 and 2 were defined as CDX-CDY+ and CDX+CDY-/+

respectively (upper right hand quadrant). Fluorescent intensity of antibody directed against the drug was then analyzed on both

lymphocyte subsets; revealing cells that express receptors bound to the drug and their level of saturation.

SAMPLETIMEPOINT

Predose

24 h post-dose

1 week post-dose

2 weeks post-dose

3 weeks post-dose

CELL SATURATIONSCHEME

0%

100%

60%

20%

0%

THEORETICALSATURATION

LEVEL

FLOW CYTOMETRIC

ANALYSIS

Targeted cellsurface receptors

Therapeutic antibody

Ungated Gated on lymphocytes

Gated on subset 1 Gated on subset 2

CD45 CDX

Anti-drug

Cells expressing receptorssaturated by the drug

Anti-drug

SSC

CDY

Coun

t

Coun

t

Lymphocytes

Subset 1

Subset 2

Exe-Fiches A3-2 volets Platine:Mise en page 1 21/05/12 20:13 Page2

DETECTION AND DOSAGE OF EXOGENOUS MOLECULES

THIS TECHNICAL NOTE DESCRIBES PLATINE’S APPROACH TO DETECTION AND DOSAGE OF EXOGENOUS MOLECULES

IntroductionOne of the major challenges during the preclinical and clinical development of a new drug is the characterization of its pharmacokinetic (PK) and pharmacodynamic (PD) properties (See table 1). Preclinical PK/PD data issuedfrom either in vitro, ex vivo or in vivo animal studies, provide the basis for insilico modeling and simulation of the human PK/PD characteristics of the drug,leading to determination of the minimum anticipated biological effect level(MABEL) and the selection of the first human dose for clinical trials [1]. Clinical PK/PD data from first clinical trials are also of outstanding importanceto confirm or update PK and PD models in order to optimize dosing regimensfor subsequent efficacy and safety phase I trials and later clinical trials [2].Among new assays developed to support recent development of new proteintherapeutics, ligand binding assays are widely used to assess PK/PD propertiesof this new class of drugs [3, 4].

Developing vaccines, monoclonal antibodies and other immuno-modulatingtherapies requires accurate assessment of the patients’ immune responseduring clinical trials. Platine designs, performs and interprets complex assays that highlight all facets of the immune response. These immuno-monitoring studies can be split into 4 investigation domains:

PHENOTYPIC AND FUNCTIONAL CHARACTERIZATION OF IMMUNECELL SUBSETS

DETECTION AND DOSAGE OF ENDOGENOUS MOLECULES

DETECTION AND DOSAGE OF EXOGENOUS MOLECULES

IMMUNOGENICITY AND CYTOTOXICITY ASSAYSPlatine Pharma Services performed this test on patient blood samples in a clinical trial in which two different dosing regimenswere compared (dose A and dose B). Samples were collected during day 1 post-dosing but also at day 7, day 14, day 21 and day28 post-dosing.The overall clear-cut results show that a full saturation of the target is limited to one day with dose A while it islasting at least a month with dose B (See figure 3).

REFERENCES1. GUIDELINE ON STRATEGIES TO IDENTIFY AND MITIGATE RISKS FOR FIRST-IN-HUMAN

CLINICAL TRIALS WITH INVESTIGATIONAL MEDICINAL PRODUCTS. COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE, E.M. AGENCY, 2007.

2. PHARMACOKINETICS/PHARMACODYNAMICS AND THE STAGES OF DRUG DEVELOPMENT:ROLE OF MODELING AND SIMULATION. CHIEN, J.Y., ET AL., AAPS J, 2005. 7(3): P. E544-59.

3. BIOANALYTICAL APPROACHES TO QUANTIFY "TOTAL" AND "FREE" THERAPEUTIC ANTIBO-DIES AND THEIR TARGETS: TECHNICAL CHALLENGES AND PK/PD APPLICATIONS OVER THECOURSE OF DRUG DEVELOPMENT. LEE, J.W., ET AL., AAPS J, 2011. 13(1): P. 99-110.

4. LIGAND BINDING ASSAYS: DEVELOPMENT, VALIDATION AND IMPLEMENTATION IN THEDRUG DEVELOMENT ARENA. MASOOD N.KHAN, JOHN W. SINDLAY, WILEY, 2010.

5. RECOMMENDATIONS FOR THE BIOANALYTICAL METHOD VALIDATION OF LIGAND-BINDINGASSAYS TO SUPPORT PHARMACOKINETIC ASSESSMENTS OF MACROMOLECULES.DESILVA, B., ET AL., PHARM RES, 2003. 20(11): P. 1885-900.

6. GUILDELINE ON BIOANAYTICAL METHOD VALIDATION. COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE E.M. AGENCY, 2011.

Platine Pharma Services - Bâtiment Domilyon, Centre d'Infectiologie, Floor 1 - 321 avenue Jean Jaurès - 69007 Lyon - FranceTe l : + 3 3 ( 0 ) 4 3 7 7 0 8 7 0 0 - F a x : + 3 3 ( 0 ) 4 3 7 7 0 6 7 9 8 - m a i l : i n f o @ p l a t i n e - l a b . c o m - w w w. p l a t i n e - l a b . c o m

FIGURE 3: Measurement of cell surface receptor saturation by the drug on patient wholeblood samples receiving different dosing regimen.

Whole blood samples from patients receiving either dose A or dose B of thenew therapeutic antibody were collectedthe day of dosing, before and 2h after dosing and on day 1, 7, 14, 21 and 28 afterdosing. Receptor saturation assays were performed within 2 days post-collectionand results are shown in the lower graph.

Conclusion

Platine successfully conducted standardized testing on this large cohort of clinical samples.The customer has now in hands the pharmacodynamic behavior of the drug related to the dose injected to patients; together withefficacy data this will help better define dosing regimen for the next clinical trials.

Dose escalatingclinical trial

Dosing and samplingschedule

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Exe-Fiches A3-2 volets Platine:Mise en page 1 21/05/12 20:13 Page1

ACTIVE BIOMARKERS | www.active-biomarkers.com | info@active-biomarkers.com

CASE STUDYCLINICAL CHARACTERIZATION OF THE PHARMACODYNAMIC PROFILE OF A MONOCLONAL ANTIBODY USING A RECEPTOR OCCUPANCY ASSAY

CONCLUSION

we were

We

We successfully