Dreaming Big and Thinking Small: Applying Medicinal

6/22/2016

We will begin momentarily at 2pm ET

Slides available now! Recordings will be available to ACS members after one week.

www.acs.org/acswebinars Contact ACS Webinars ® at [email protected]

1

Have Questions?

“Why am I muted?” Don’t worry. Everyone is muted except the presenter and host. Thank you and enjoy the show.

Type them into questions box! Contact ACS Webinars ® at [email protected]

2

1

6/22/2016

Have you discovered the missing element?

http://bit.ly/ACSmember Find the many benefits of ACS membership!

3

Benefits of ACS Membership Chemical & Engineering News (C&EN) The preeminent weekly news source. NEW! Free Access to ACS Presentations on Demand® ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events. NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.

http://bit.ly/ACSmember

4

2

6/22/2016

Let’s get Social…post, tweet, and link to ACS Webinars during today’s broadcast!

facebook.com/acswebinars

@acswebinars

Search for “acswebinars” and connect!

5

How has ACS Webinars® benefited you? Quote in reference to: http://www.acs.org/content/acs/en/acs-webinars/drug-discovery/drug-career.html

“An informative and inspirational webinar. Medicinal chemists must embrace the challenge of providing efficacious drugs for all diseases as we move towards personalized medicines.”

Tito Akindele, Ph.D. Researcher, Nagase Laboratory of Medicinal Chemistry International Institute for Integrative Sleep Medicine (IIIS) World Premier International Research Center Initiative (WPI) University of Tsukuba, Japan

Be a featured fan on an upcoming webinar! Write to us @ [email protected]

6

3

6/22/2016

facebook.com/acswebinars @acswebinars youtube.com/acswebinars

Search for “acswebinars” and connect! 7

Learn from the best and brightest minds in chemistry! Hundreds of webinars presented by subject matter experts in the chemical enterprise. Recordings are available to current ACS members about one week after the Live broadcast date. www.acs.org/acswebinars ®

Broadcasts of ACS Webinars continue to be available to the general public LIVE every Thursday at 2pm ET!

www.acs.org/acswebinars

8

4

6/22/2016

ChemIDP.org

9

Join the ACS Division of Medicinal Chemistry Today!

For $25 ($10 for students), You Will Receive: • A free copy of our annual medicinal chemistry review volume (over 600 pages, $160 retail price) • Abstracts of MEDI programming at national meetings • Access to student travel grants and fellowships Find out more about the ACS MEDI Division www.acsmedchem.org

10

5

6/22/2016

Program Themes

Featured Speakers

•

Advancing Product Development through Novel Technology: Material Science, Engineering & Analytical Methodology

•

Making New Delivery Modalities a Reality: Peptides, Proteins & Conjugates

•

Enhancing Patient Lives through Accelerated Drug Development

•

Paving the Way for Precision Medicine: Innovation & Implementation

• • • •

Daniel A. Fletcher, Ph.D. (U. California at Berkeley) diagnostic medical devices to investigate the biophysical mechanisms of disease Frederick Balagadde, Ph.D. (K-RITH Durban, South Africa) - microfluidic systems to increase affordable healthcare access James Olson, M.D., Ph.D. (Fred Hutchinson Cancer Research Center) - new cancer therapies for children with brain tumors Susan Hershenson, Ph.D. (The Bill & Melinda Gates Foundation) - technical expertise & strategic guidance for the therapeutics projects

Find out more about the AAPS www.aaps.org/annualmeeting

11

2016 Drug Design and Delivery Symposium

http://bit.ly/2016ddds

12

6

6/22/2016

Upcoming ACS Webinars www.acs.org/acswebinars Thursday, June 30, 2016

Ice Cream Chemistry Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison Bill Courtney, Culinary Chemist

Thursday, July 7, 2016

The Chemistry of Sight: Material Innovations in Eye Care and Contact Lenses Heather Sheardown, Professor of the Department of Chemical Engineering and Canada and Research Chair in Ophthalmic Biomaterials, McMaster University Mark Jones, Executive External Strategy and Communications Fellow, Dow Chemical

Contact ACS Webinars® at [email protected]

13

2016 Drug Design and Delivery Symposium “Applying Medicinal Chemistry Strategy to Antibody-Drug-Conjugates”

Peter D. Senter

L. Nathan Tumey

Vice President of Chemistry, Seattle Genetics

Associate Research Fellow, Pfizer, Inc.

Slides available now! Recordings will be available to ACS members after one week

www.acs.org/acswebinars The 2016 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS

14

7

6/22/2016

Dreaming Big and Thinking Small: Applying Medicinal Chemistry Strategy to Antibody-Drug-Conjugates

L. Nathan Tumey [email protected]

15

Antibody Drug Conjugates: Targeted Cancer Chemotherapy

Nature Biotechnology, 2012, 30, 631–637.

16

8

6/22/2016

The Big and the Small: ADC design overview Payload Design • Enzyme/target potency • Cytotoxicity • Efflux • Permeability

Antigen Selection / Antibody Design • Target expression • Internalization • Binding affinity • PK (FcRn binding)

Linker Design • Cleavable/noncleavable • Hydrophobicity / aggregation • Efflux • Permeability

Bioconjugation • ADC biophysical properties • ADC heterogeneity • ADC PK exposure • ADC stability

17

Payload chemistry: What payload do we attach? DNA

RNA

Other MOAs

IC50 (nM)

MTI

Payload Series 18

9

6/22/2016

Payload chemistry: What payload do we attach? Selection Criteria

•Potency/Cytotoxicity •Mechanism of Action •Required target occupancy

Payload Sources Total Synthesis

•ADME properties •Synthetic Tractability/Scalability •Handles for Linker Attachment

Fermentation/Isolation

Spliceostatins IC50’s = 0.05-0.6 nM RNA Splicing Inhibitor Low efflux ratio

Auristatins IC50’s = 0.07-0.21 nM Tubulin binder High efflux ratio

Tubulysins IC50’s = 0.1-0.8 nM Tubulin binder CBI Dimer IC50’s = 0.0007 – 1 nM Low efflux ratio DNA Double strand alkylator Low efflux ratio

Calicheamicin IC50’s = 0.003-1.7 nM DNA Double strand breakage High efflux ratio

19

Linker Chemistry: How do we release a payload? Noncleavable

Internalization to lysosome Complete ADC catabolism

Cleavable

Cathepsin cleavage site

Internalization to lysosome

20

10

6/22/2016

Linker Chemistry: How do we release a payload? Intracellular phosphatases

Jeffrey Kern, Phil Brandish et. al. JACS, 2016

lysosomal glucoronidase

Bioconjugate Chem., 2006, 17, 831-840.

Cancer Chemother. Pharmacol., 2008, 1027-35. Acidic hydrolysis Intracellular reduction 21

Conjugation Chemistry: How do we attach a payload? Lysine conjugation

Hinge cysteine conjugation

Activated ester (often NHS)

Electrophile (often maleimide)

+

Site-specific conjugation

+ +

+ … 22

11

6/22/2016

Conjugation Chemistry: How do we attach a payload? Site specific conjugation: 3 common approaches Engineered Cysteine

Unnatural Amino Acids

Enzymatic Conjugation

23

Stability of maleimide conjugates

Deconjugation

24

12

6/22/2016

Audience Trivia Question ANSWER THIS QUESTION ON THE BLUE SCREEN IN ONE MOMENT So how big of a problem is this? Approximately what % of drug is lost from a typical maleimide ADC during 1 week in circulation? • About one tenth • A little less then one third • About half • A little less than two thirds

25

Audience Trivia Question ANSWER THIS QUESTION ON THE BLUE SCREEN IN ONE MOMENT So how big of a problem is this? Approximately what % of drug is lost from a typical maleimide ADC during 1 week in circulation? • About one tenth • A little less then one third • About half • A little less than two thirds

Answer: 60% - almost all of it going to serum albumin (note that the T1/2 of an ADC in humans is ~1 week!)

26

13

6/22/2016

Stability of maleimide conjugates To impart stability: Site dependent

1) Intentionally open the maleimide Tumey L. N. et al., Bioconjugate Chem. 2014, 25(10), 1871-1880 Lyon R. P. et al., Nature Biotech., 2014, 32(10), 1059-1062

2) Use an alternative electrophile Barbas, C.F. et al., Angew. Chem. 2013, 12592.

3) Attach to a stable site

X

Ring-opening (improved stability)

Deconjugation

27

Site plays a major role in the conjugate stability

% ring-opening % DAR loss

In vivo DAR profile

28

14

6/22/2016

Site of conjugation has little effect on in vitro potency The payload-linker drives the in vitro cytotoxicity – not the site of attachment.

29

Site of conjugation impacts ADC hydrophobicity

TG-FC

HIC RRT

Hydrophobic interaction chromatography (HIC)

ADC hydrophobicity is a function both of the LP and of the site of conjugation 30

15

6/22/2016

Hydrophobicity has an impact on ADC PK exposure Robert Lyon et. al., Nature Biotechnology, 2015, 733–735

Hydrophobic linkerpayloads can result in reduced ADC exposure

31

Site of conjugation can impact ADC PK exposure k183C

Concentration (ug/mL)

Rat PK study Kappa-K183C vc0101 (tAb) Kappa-K183C vc0101 (ADC) Fc-L443C vc0101 (tAb) Fc-L443C vc0101 (ADC)

HIC rrt = 1.35 (AUC = 28500 mg*h/mL)

HIC rrt = 1.91 (AUC = 11000 mg*hr/mL)

Time (hours)

443C 32

16

6/22/2016

% cleavage

% Cleavage @20 mins

Site impacts payload release kinetics

HIC RRT

Higher HIC retention = faster cleavage

Audience Trivia Question ANSWER THIS QUESTION ON THE BLUE SCREEN IN ONE MOMENT Faster cathepsin-mediated linker cleavage in the lysosome should result in: • Increased cytotoxicity

• Decreased cytotoxicity • Little or no effect on cytotoxicity

34

17

6/22/2016

Audience Trivia Question ANSWER THIS QUESTION ON THE BLUE SCREEN IN ONE MOMENT Faster cathepsin-mediated linker cleavage in the lysosome should result in: • Increased cytotoxicity • Decreased cytotoxicity

• Little or no effect on cytotoxicity Answer: Little or no effect on cytotoxicity

35

Site impacts payload metabolism

Lower efficacy than was anticipated – rapid cleavage of acetate observed in vivo and in vitro.

Inactive metabolite!

36

18

6/22/2016

100%

% Acetate cleavage at 2h

Mouse Plasma % Parent remaining

Site impacts payload metabolism

334C

80%

392C

60% 40%

50% R² = 0.9353

40% 30% 20% 10% 0% 1

20% 0% 0

20

40

60

1.1

1.2

1.3

1.4

HIC RRT

347C 388C k183C 443C

80

Lesson Learned: Sites that result in minimal HIC retention are resistant to in vitro enzymatic metabolism.

Time (h)

ACS Med.Chem.Letters, 2016, in press

Site impacts payload metabolism Improved stability = improved efficacy Tumor volume (mm3)

1600 1200

800

Hinge conjugate (DAR4) (rapid in vivo metabolism)

400

334C conjugate (DAR2) (no in vivo metabolism)

0 0

20

40

60

80

Days

ADC biophysical properties  in vitro metabolism  in vivo efficacy / metabolism

38

19

6/22/2016

Site impacts conjugatability: Uncialamycin SEC after attempted conjugation to Tras-A114C:

39

Site impacts conjugatability: Uncialamycin A114C:

Mutant K246C K334C Q347C Y373C S375C

LCMS DAR 0.8 1.5 1.4 1.2 1.8

%Agg 1% 2.6% 21% 0% 0.6%

% Right shifted 0% 0% 63% 36% 0%

E380C E388C K392C N421C L443C kap-A111C kap-K149C

1.8 1.3 2 1.4 1.8 0.7 0.9

0% 0% 2.5% 77% 87% 0% 3%

100% (only slight) 68% 2.5% 0% 0% 50% 50%

kap-K183C kap-K188C

1.9 1.4

0% 11%

87% (only slight) 39%

HIC RRT 1.24 1.28 1.87 1.34 1.59

Screening of sitemutants enabled the conjugation of LPs that were otherwise intractable. All 4 uncialamicin LPs were successfully attached to the 392 and 375 sites.

40

20

6/22/2016

Summary •

ADC discovery efforts require a seamless integration of large-molecule design and small molecule design.

•

A “toolbox” of conjugation sites allows for rapid optimization to solve conjugation, stability, and metabolism problems.

•

ADC biophysical properties are becoming an important component of predicting in vitro and in vivo ADC stability.

Key Take-Home Message: We are gradually moving away from empiricism and towards a “prospective” set of rules for ADC design.

41

The next horizon: Growing interest in non-oncology ADCs

Merck Jeffrey Kern, Phil Brandish et. al. JACS, 2016

LCK inhibitor

Peter Schultz JACS, 2015

Roche/Genentech Thomas Pillow et. al. Nature, 2015 42

21

6/22/2016

Acknowledgements Worldwide Medchem Chris O’Donnell Edmund Graziani Chakrapani Subramanyam Russell Dushin Frank Koehn Beth Vetelino Sujiet Puthenveetil Jeff Casavant Andreas Maderna Anokha Ratnayake Zecheng Chen Matt Doroski Hud Risley Alex Porte Gary Filzen Ludivine Moine Dahui Zhou Ken Dirico

Carolyn Leverett Jesse Teske S. Chetan Sukuru Jack Bikker Melissa Wagenaar Pharmacokinetics, Dynamics, and Metabolism Frank Barletta Jo-Ann Wentland Tracey Clark Mauricio Leal Xiaogang (Sean) Han Brian Rago Fengping Li Cong Wei Steve Hansel

Oncology Research Hans Peter Gerber Puja Sapra Pavel Strop Kathy Delaria Frank Loganzo Kiran Khandke Manoj Charati William Hu Sylvia Musto Judy Lucas Nadira Prashad Ellie Muszynska Jacob Vineberg

Global Biologic Technologies Will Somers Lioudmila Tchistiakova Kim Marquette Sadhana Jain Mark Krebs Madan Katragadda Rita Agostinelli Nicole Piche-Nicholas Ryan Jackobek Eric Bennett Amy Tam Laura Lin Eric Sousa Tao He

43

Backup slides

44

22

6/22/2016

The ideal scenario “The Universe of Sites”

Small set of highly preferred sites

Biological Stability

45

2010-2011: Site may have impact on PK Antibody/Time (anti-IgG)

ADC/Time (anti-MMAD)

A114C E380C* L398C L443C V422C Conventional* Control Ab

The 380C-mcMMAD has good tAb PK but poor ADC PK. Why??

46

23

6/22/2016

Using ring-opening to block deconjugation Blocking deconjugation: Forced ring opening Tumey L. N. et al., Bioconjugate Chem., 2014, 25(10), 1871-1880

Blocking deconjugation: Spontaneous ring opening Lyon R. P. et al., Nature Biotech., 2014, 32(10), 1059-1062

Christie, R. J. et al, J. Controlled Release (2015), Ahead of Print.

47


Peter D. Senter

L. Nathan Tumey





48

24

6/22/2016

2016 Drug Design and Delivery Symposium

http://bit.ly/2016ddds

49






50

25

6/22/2016


Peter D. Senter

L. Nathan Tumey





Program Themes •

Advancing Product Development through Novel Technology: Material Science, Engineering & Analytical Methodology

•

Making New Delivery Modalities a Reality: Peptides, Proteins & Conjugates

•

Enhancing Patient Lives through Accelerated Drug Development

•

Paving the Way for Precision Medicine: Innovation & Implementation

51

Featured Speakers • • •

•

Daniel A. Fletcher, Ph.D. (U. California at Berkeley) diagnostic medical devices to investigate the biophysical mechanisms of disease Frederick Balagadde, Ph.D. (K-RITH Durban, South Africa) - microfluidic systems to increase affordable healthcare access James Olson, M.D., Ph.D. (Fred Hutchinson Cancer Research Center) - new cancer therapies for children with brain tumors Susan Hershenson, Ph.D. (The Bill & Melinda Gates Foundation) - technical expertise & strategic guidance for the therapeutics projects

Find out more about the AAPS www.aaps.org/annualmeeting

52

26

6/22/2016

Join the ACS Division of Medicinal Chemistry Today!

For $25 ($10 for students), You Will Receive: • A free copy of our annual medicinal chemistry review volume (over 600 pages, $160 retail price) • Abstracts of MEDI programming at national meetings • Access to student travel grants and fellowships Find out more about the ACS MEDI Division www.acsmedchem.org

53

How has ACS Webinars® benefited you? Quote in reference to: http://www.acs.org/content/acs/en/acs-webinars/drug-discovery/drug-career.html

“An informative and inspirational webinar. Medicinal chemists must embrace the challenge of providing efficacious drugs for all diseases as we move towards personalized medicines.”

Tito Akindele, Ph.D. Researcher, Nagase Laboratory of Medicinal Chemistry International Institute for Integrative Sleep Medicine (IIIS) World Premier International Research Center Initiative (WPI) University of Tsukuba, Japan

Be a featured fan on an upcoming webinar! Write to us @ [email protected]

54

27

6/22/2016

facebook.com/acswebinars @acswebinars youtube.com/acswebinars

Search for “acswebinars” and connect! 55

Benefits of ACS Membership Chemical & Engineering News (C&EN) The preeminent weekly news source. NEW! Free Access to ACS Presentations on Demand® ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events. NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.

http://bit.ly/ACSmember

56

28

6/22/2016

ACS Webinars® does not endorse any products or services. The views expressed in this presentation are those of the presenter and do not necessarily reflect the views or policies of the American Chemical Society.


57






58

29

Dreaming Big and Thinking Small: Applying Medicinal

Recommend Documents