Towards Addressing Informatics Challenges Presented by Antibody

Towards Addressing Informatics Challenges Presented by Antibody Drug Conjugates

250th ACS National Meeting, Boston MA

August 2015

Chetan Sukuru Principal Scientist.

Medicinal Chemistry (Oncology East), Pfizer, Groton CT

Abstract

Authors: Sai Chetan Sukuru , Tianhong Zhang, Lawrence Tumey, Elwira Muszynska, Megan Tran and Frank Loganzo Recent advances and drug approvals have led to an increased interest in Antibody Drug Conjugates (ADCs). Even though a lot of promising preclinical and clinical data has been reported on numerous ADCs, there is still a paucity of in silico descriptors and tools that could help navigate the molecular complexity of ADCs as well as analyze the data around them. To tackle the informatics challenges arising from new ADC discovery projects, we have developed a novel in silico tool called Antibody Conjugate Tracker (ACT). ACT is designed to efficiently characterize each ADC and its molecular components, namely the antibody, linker-payload and payload. The ACT provides a unique in silico environment with structured metadata that enables comprehensive data analytics on ADCs. Based on the versatile applications and impact of this tool in house – from compound registration and management to data visualization and analysis, we propose novel descriptors to parse and analyze ADC data that could improve our understanding and accelerate the discovery of potential therapeutic ADCs.

Pfizer Confidential │ 2

Quick Introduction to an ADC: Antibody Drug Conjugate


Gerber et al., Nat Prod Rep, 2013, 30(5): 625-39

Antibody Drug Conjugate: ADC at a Glance

4

Antibody

Linker Payload (LP)

Conjugation Site

Linker

Payload

(Protease) Cleavable ADC: An Example and a Guided Tour


Released species (free payload)

Sapra et al., Expert Opin Investig Drugs, 2011, 20(8): 1131-49

mAb

spacer Val Cit

cleavable linker payload

Rising Interest in ADC Development


Jackson and Stover, Pharma Res, 2014 http://www.ncbi.nlm.nih.gov/pubmed/25339341


Jackson and Stover, Pharma Res, 2014 http://www.ncbi.nlm.nih.gov/pubmed/25339341

More than 40 ADCs in the Clinic at present

PubMed Search for ADC Literature


Exponential increase in published literature for “ADC” in the last few years

• However, similar PubMed search for the following yields very few results: – “Antibody Drug Conjugate” and “Informatics” – 2 articles – “Antibody Drug Conjugate” and “Computational” – 7 articles – “Antibody Drug Conjugate” and “in silico” – 9 articles

Data until 2014

Rapid Increase in ADCs Poses an Informatics Challenge

9

ORU-PR & WWMC-GTN

Required building an informatics infrastructure to support this growth

Severe Limitations of Frequently Used Spreadsheets for ADCs

10

Single spreadsheet for each component antibody, linker payload and ADCs; ADC sheet had 100+columns and 800 rows of data

Recognized Informatics Infrastructure Gap for ADCs

Small molecule • Pfizer has a well defined

process and infrastructure for small molecule o Registration-GeCR o Sample management-

Mattrack o Bio Assays-GePR/

Bioloader, PP, Biobook etc o Data retrieval/SAR/D360

ADCs (Biotherapeutics)

• Infrastructure gap: registration, compound inventories, sample management and a comprehensive data retrieval process

11

Antibody Conjugate Tracker: ACT

• Purpose: – To track all ADCs and their components. – To register ADCs with Corporate IDs

• New ADC database created by Bioconjugation groups & Pfizer Business Technology

– Built upon PMR (Pfizer Macromolecule Registration system) software infrastructure

– Completely customized specifically for ADC workflow

– Antibody, LP, & ADC management system • End users can:

– Obtain ADC analytical data – Make Bioconjugation requests – Perform in silico data analytics

• Replaces: – ADC Inventory Excel file (for ADC info) – Emailing Excel spreadsheets for conjugation

requests Pfizer Confidential │ 12

Enterprise relational database approach

Java web start-enabled desktop application built on top of eTracker framework

Tianhong Zhang (Pfizer Research Informatics, Business Technology) also presenting in COMP #3: HELM: An open standard for complex polymeric structures (Sunday, 8/16, 10:05 AM, Room 157A)

ACT: Snapshot


Details of the selected row (ADC)

Parsing an ADC into its Molecular Components

• Each registered ADC at Pfizer gets the following four corresponding corporate IDs


Pare

nt A

DC

Antibody

Linker-Payload

Payload A

DC

Cor

pora

te ID

Structured Metadata at the ADC level:

ADC Full name

Conjugation Purpose In vitro In vivo Safety Experimental

Conjugation Chemistry

Cys – Conventional Cys – Site-Specific Lys – Random Etc.

Conjugate Amino Acid

[Chain] [Res] [Seq#]

• Note that comprehensive (experimental) analytical data on ADCs is also recorded in the database.

Visualizing ADC Metadata: An Example

Using the ACT data to quickly visualize the distribution of ADCs for select conjugation chemistries and purposes End users can further analyze the distribution of Cys – site-sp ADCs across different sites


All plots in this presentation have been generated in TIBCO Spotfire DXP

Pare

nt A

DC

Antibody

Linker-Payload

Payload

Structured Metadata at the Antibody Level


AB Full Name: [Antigen]-[AbClone]-[Ab Properties]-[Species Isotype]

AB Corporate ID

Using the ACT data to quickly visualize the distribution of ADCs based on the antibody species

End users can also analyze a similar distribution based on antigen name, clone, mutation, etc.

Structured Metadata at the Linker-Payload Level


Pare

nt A

DC

Antibody

Linker-Payload

Payload

LP Corporate ID

LP Short Name: [Linker Name]_[Payload Class Abbrev]_[Payload ID] Linker Type: Non cleavable; Cleavable – proteolytic; Cleavable – hydrolytic, etc.

Using the ACT data to quickly visualize the distribution of ADCs based on Linker Type

Structured Metadata at the Payload Level


Pare

nt A

DC

Antibody

Linker-Payload

Payload

Payload Corporate ID

Payload Class: Auristatin; Maytansine; Calicheamicin; etc. Payload Mechanism: Tubulin; DNA; etc.

Using the ACT data to quickly visualize the distribution of ADCs based on Payload Mechanism

End users can further analyze the distribution of ADCs with different Payload Classes within a Payload Mechanism (e.g. Tubulin)

*Note that only select examples have been shown in this plot to illustrate the payload-level metadata

Query and Retrieve Data

• ACT has been integrated with D360

• Enables incorporation of ACT fields

to query for assay data in D360

• Coupled with compound structure search (Payload or Linker-Payload), provides a powerful tool for querying activity data of ADCs


Core information gateway for accessing discovery data for Pfizer Research Community

Developed by Certara

Using ACT Descriptors for ADC in vitro Data Visualization: Payload Perspective


ADC

pot

ency

in A

ntig

en

Expr

essi

ng C

ell L

ine

IC50

(nM

)

Payload Class A B C D E F G

Colored by Payload Mechanism Shaped by Payload Class

*Note that only select examples have been shown in this plot to illustrate the payload-level metadata

Using ACT Descriptors for ADC in vitro Data Visualization: Payload & Linker Perspective


ADC

pot

ency

in A

ntig

en

Expr

essi

ng C

ell L

ine

IC50

(nM

)

Payload Class A B C D E F G

Colored by Linker Type Shaped by Payload Class

*Note that only select examples have been shown in this plot to illustrate the payload- and linker-level metadata

Using ACT Descriptors for ADC in vivo Data Visualization: Antibody Perspective

Structured metadata in ACT enables in vivo data comparison of a given Linker-Payload across different antibodies (program/antigen specific)


*It is important to note the caveats originating from dose-level and tumor xenograft models when comparing in vivo performance of LPs/ADCs

Summary

• Despite the rising interest in ADCs, there is still a gap in the informatics infrastructure/technology to support their discovery and development

• We have attempted to bridge the gap and address some of the informatics challenges presented by ADCs

• Structured metadata incorporated in the Antibody Conjugate Tracker not only keeps track of all the ADCs but also enhances in silico data analytics and visualization

• Similar approach with standardized descriptors could help develop substance identifiers for other chemically-modified biologics too


Limitations and Challenges: Future Development

• Even though ACT is a step forward to address the informatics challenges presented by ADCs, improvements in substance identifiers and structural descriptors for antibodies, especially for mutants of the same antibody, are needed to enable the next level of data analytics

• ADCs provide the unique opportunity to bridge small molecule (payload/LP SAR) cheminformatics and target antigen (expression levels) bioinformatics. Advancing informatics to build this bridge will be valuable for project teams making decisions on ADC programs.


Acknowledgements

• ACT Development Team – Frank Loganzo (ORU: Oncology Research Unit) – Elwira Muszynska (ORU) – Megan Tran (Research Informatics, BT) – Tianhong Zhang (Research Informatics, BT) – L. Nathan Tumey (WWMC)

• WorldWide Medicinal Chemistry – Chris O’Donnell (ADC Chemistry Leadership) – Russell Dushin – Chakrapani Subramanyam – Martin Edwards (Oncology Chemistry Leadership)

HP Gerber (ORU Leadership) Dave Rubin (Legal)


Thank You!

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Towards Addressing Informatics Challenges Presented by Antibody