targeted approach using biomarkers, adc's the next frontier

Targeted Approach using Biomarkers,

ADC's The Next Frontier

David O’Malley, M.D.

Ovarian Cancer - Clinical Trial Advisor

GOG Partners

Director, Division of Gyn Oncology

Professor, Department of OB/Gyn

The Ohio State University

James CCC

Objectives

• Understanding targeted drug therapy (ADCs) as a treatment for patients with ovarian cancer

• Structure

• MOA

• Effective Delivery Considerations

• Targets

• Agents

Verbal Disclosure (2 years)

• Abbvie• Agenus• Ambry• Amgen• AstraZeneca • Clovis• Elevar• Immunogen• Iovance• Janssen/J&J• Merck• Mersana• Myriad Genetics• Novartis• Novocure• Regeneron • Roche/Genentech• SeaGen• Tarveda• Tesaro/GSK

Consultation and/or Honorarium Institutional Research Support

• Abbvie• Agenus• Amgen• AstraZeneca • Clovis• Immunogen• Iovance• Janssen/J&J• Merck• Mersana• Novartis• Novocure• Regeneron • Roche/Genentech• SeaGen• Tesaro/GSK• EMD Serono• Ergomed• Ajinomoto • GOG Foundation• Serono Inc,

FDA-Approved Drugs for Ovarian Cancer

2020201020001960 19801970

1960

Cyclophosphamide (1959)

Melphalan

(1964)

Etoposide

(1983)

Carboplatin

(1989)

Altretamine

(1990)

Docetaxel

(1996)

Topotecan

ROC (1996)

PLD-Accelerated

ROC (1999)*

PLD-Full

ROC (2005)

Gemcitabine/Carboplatin

PlSOC (2006)

Olaparib

gBRCAmut ROC > 3-L (2014)

Chemo + Bevacizumab (2014) PlROC

Rucaparib gBRCAmut/

sBRCAmut ROC > 2-L (2016)

Chemo + Bevacizumab

PlSOC (2016)

Olaparib

Maintenance PlSOC (2017)

Niraparib


Pembrolizumab

MSI/dMMR ROC (2017)

Cisplatin

(1978)

1990

Paclitaxel

Full (1998)Paclitaxel

Accelerated

(1992)

Rucaparib


Bevacizumab

1-L + Maintenance (2018)

1970 1980 1990 2000 2010

Olaparib

gBRCAmut 1-L

Maintenance (2018)

Niraparib

HRD ROC > 3-L (2019)

2020

12+ Approvals since Nov 2014

More approvals in the last 6 years than the prior 60 years combined

Niraparib

1-L Maintenance (2020)

Olaparib + Bev

1-L Maintenance (2020)

https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed on 7 March 2021

https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf

The Era of Targeted Therapy in Ovarian Cancer is Here

Drug Maintenance Later-line Treatment

Olaparib 1 SOLO-2 (BRCA mut)

Study 19

(Aug 17, 2017)

SOLO-1 (BRCA mut)

(Dec 19, 2018)

With Bev

PAOLA-1 (HRD)

(May 8, 2020)

Study 42 (BRCA mut)(Dec 19, 2014)

Rucaparib 2,3 ARIEL3

(April 6, 2018)

Study 10 (BRCA mut)ARIEL2 (BRCA mut)

(Dec 19, 2016)

Niraparib 4 NOVA

(Mar 27, 2017)

PRIMA

(April 29, 2020)

QUADRA

(Oct 23, 2019)

Bevacizumab5 GOG218

(June 13, 2018)

OCEANS – GOG213

(Dec 6, 2016)

AURELIA

(Nov 14, 2014)

1. Olaparib package insert. AstraZeneca Pharmaceuticals LP; 2020.2. FDA. Summary Review for Regulatory Action: Olaparib.

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000SumR.pdf. Approval date December 19, 2014. Accessed April 10, 2018.

3. Rucaparib package insert. Clovis Oncology, Inc; April 2018.4. Niraparib package insert. TESARO, Inc; August 2020.5. https://www.drugs.com/history/avastin.html

Antibody Structure

• Antigen

• Linker

• Payload

Hoffmann RM, Coumbe BGT, Josephs DH, Mele S, Ilieva KM,

Cheung A, et al. Antibody structure and engineering

considerations for the design and function of Antibody Drug

Conjugates (ADCs). Oncoimmunology. 2018, VOL. 7, NO. 3,

e1395127

Antibody Structure• Antigen Properties

• High homogenous expression on tumor cells

• Low/no expression on normal cells

• Antigen-antibody binding is the first mechanistic step in a cascade of events

• The target antigen must be well internalized by receptor mediated endocytosis

• Should not be down-regulated by endocytosis or by the effects of repeated stimulation during treatment

• Minimum antigen expression threshold is required for ADC efficacy

Hoffmann RM, Coumbe BGT, Josephs DH, Mele S, Ilieva KM, Cheung A, et al. Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates

(ADCs). Oncoimmunology. 2018, VOL. 7, NO. 3, e1395127

Antibody Structure



• Payload• Drugs that are suitable for

antibody conjugation and deliver an effective cytotoxic dose

• The most commonly utilized payloads in ovarian cancer are:• Monomethyl auristatin E

(MMAE/Vedotin)

• DM4 (Ravtansine/Soravtansine)

• High potency in the picomolar range is key to therapeutic benefit as payload delivery is limited by the drug to antibody ratio (DAR)

• Bystander effect: membrane permeable allows for diffusion from targeted tumor cells into neighboring cells

Antibody Structure



• Linker Properties• Forms the chemical connection

between the antibody and payload

• Main function is to stabilize the cytotoxic payload while in circulation and allowing release of the payload when the ADC is antigen-bound or internalized

• A majority of linkers are designed to allow for payload release after internalization of the ADC• Cleavable: releases the active

metabolite intracellularly after cleavage via enzymes, hydrolysis, or reduction of disulfide bonds

• Non-cleavable: complete degradation of the antibody backbone before the active metabolite is releases

Antibody Structure



• Linker Properties• Forms the chemical connection

between the antibody and payload

• Main function is to stabilize the cytotoxic payload while in circulation and allowing release of the payload when the ADC is antigen-bound or internalized

• A majority of linkers are designed to allow for payload release after internalization of the ADC• Cleavable: releases the active

metabolite intracellularly after cleavage via enzymes, hydrolysis, or reduction of disulfide bonds

• Non-cleavable: complete degradation of the antibody backbone before the active metabolite is releases

Choice of linker is also a key determinant of

biodistribution, therapeutic activity and

pharmacokinetics and represents a fine

balance between therapeutic value/toxicity

and distribution

Drug to antibody ratio (DAR)

• Determined by the linker utilized and is an essential factor affecting therapeutic toxicity with an increased DAR resulting in increased toxicity.

• While a high DAR increases the potency of the ADC, it can adversely affect pharmacokinetics and distribution.

• Historically, the DAR has been limited to an average range of 2-4 because ADCs with a higher DAR were prone to increased plasma clearance largely due to hepatic ADC uptake.

• Position and number of payloads bound to the antibody can have profound effects on:

• the binding to the antigen,

• the aggregation of the ADC,

• the pharmacokinetic characteristics of the antibody construct,

• the safety profile of the ADC

• Improving the antibody site for linker conjugation has been greatly enhanced through advancements in protein engineering

Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG, et al. Effects of drug loading on the antitumor

activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10:7063-70.

Lyon RP, Bovee TD, Doronina SO, Burke PJ, Hunter JH, Neff-LaFord HD, et al. Reducing hydrophobicity of

homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat Biotechnol.

2015;33:733-5.

Sun X, Ponte JF, Yoder NC, Laleau R, Coccia J, Lanieri L, et al. Effects of Drug-Antibody Ratio on

Pharmacokinetics, Biodistribution, Efficacy, and Tolerability of Antibody-Maytansinoid Conjugates. Bioconjug

Chem. 2017;28:1371-81.

Hamblett, K.J. Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate.

Clin. Cancer Res. 2004, 10, 7063–7070

Mechanism of Action1. The ADC travels through the systemic

circulation to the tumor tissue

2. The antibody binds to the target antigen on the cell surface

3. The ADC complex is then internalized (majority, but not all ADCs)

4. If the ADC has a cleavable linker this is cleaved releasing the cytotoxic payload intracellularly

5. If the linker is non-cleavable, lysosomal degradation of the antibody backbone occurs with release of the cytotoxic payload

6. Microtubule inhibition or other action occurs via binding of the cytotoxic payloads to tubulin (specific to cytotoxic payload utilized)

7. Cell death/apoptosis

8. Bystander Effect - Diffusion of cytotoxic payload across the cell membrane can result in cell death of neighboring cells

Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-Drug Conjugate-Based Therapeutics:

State of the Science. J Natl Cancer Inst. 2019;111:538-49.

Calo CA, O'Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer.

Expert Opin Biol Ther. 2020 Jun 8:1-13. doi: 10.1080/14712598.2020.1776253. Online

ahead of print. PMID: 32463296




3. The ADC complex is then internalized (majority, but not all ADCs)

4. If the ADC has a cleavable linker this is cleaved releasing the cytotoxic payload intracellularly

5. If the linker is non-cleavable, lysosomal degradation of the antibody backbone occurs with release of the cytotoxic payload

6. Microtubule inhibition or other action occurs via binding of the cytotoxic payloads to tubulin (specific to cytotoxic payload utilized)

7. Cell death/apoptosis

8. Bystander Effect - Diffusion of cytotoxic payload across the cell membrane can result in cell death of neighboring cells






Target Antigens

Target antigen Function Expression ADCFolate receptor alpha Transmembrane protein involved in transport of

folate into cells necessary for metabolism, DNA

synthesis, repair, and proliferation

Ovarian: 80-96%

Endometrial: 41%

Mirvetuximab soravtansine

STRO-002

MORAb-202

NaPi2b Sodium-dependent phosphate transport protein

expressed in epithelial cells.

Ovarian: 80-100% Lifastuzumab vedotin

XMT-1536

Tissue Factor Thromboplastin or factor III, involved in extrinsic

coagulation pathway leading to generation of

thrombin/clot formation.

Ovarian: 96%

Endometrial: 15%

Cervical: 34%

Tisotumab vedotin

Mesothelin Hypothesized to be involved in cell adhesion.

Expressed on mesothelial cells.

Ovarian: 60-88% Anetumab ravtansine

DMOT4039A

BMS-986148

MUC16 Transmembrane protein with role in

adhesion/peritoneal metastases. CA-125

represents the extracellular, cleaved portion.

Ovarian: 80% DMUC4064A

Calo CA, O'Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer. Expert Opin Biol Ther. 2020

Jun 8:1-13. doi: 10.1080/14712598.2020.1776253. Online ahead of print. PMID: 32463296

ADC Target Antigen/

Antibody

Cytotoxic Payload and

mechanism of action

Linker DAR Phase of

developmentMirvetuximab soravtansine

(ImmunoGen, Inc)

Folate receptor α

Humanized IgG1 (M9346A)

Soravtansine (Maytansinoid

DM4)

Microtubule inhibitor

Sulfo-PDB 3-4 Phase III

STRO-002 (Sutro

Biopharma, Inc.)

Folate receptor α

Human anti-FRα IgG1 antibody (SP8166)

Proprietary 3-aminophenyl

hemiasterlin agent: SC209

Proprietary tubulin-targeting

payload

Proprietary cleavable

linker: SC239

4 Phase I dose

escalation/

expansion ongoing

MORAb-202 (Eisai Inc.)

(NCT03386942)

Folate receptor α

Humanized anti-human FRα farletuzumab

Eribulin mesylate


Cathepsin B-cleavable

linker

4 Phase I ongoing

XMT-1536

(Mersana Therapeutics)

(NCT03319628)

NaPi2b

Humanized monoclonal

antibody (SLC34A2)

Proprietary auristatin

derivative (auristatin F-HPA)


Proprietary hydrophilic

polymer scaffold

10-12 Phase I dose

escalation/

expansion ongoing

Lifastuzumab vedotin

(LIFA/DNIB0600A)

(Genentech, Inc.)

NaPi2b

Humanized monoclonal

antibody (SLC34A2)

MMAE


Cleavable

maleimidocaproyl-valyl-

citrullinyl-p-

aminobenzyloxycarbonyl

(mc-val-cit-PABC)

3-4 Randomized phase

II completed; further

development

discontinued

Calo CA, O'Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer. Expert Opin Biol Ther. 2020 Jun 8:1-13. doi: 10.1080/14712598.2020.1776253. Online ahead of print. PMID: 32463296

ADC Target Antigen/

Antibody

Cytotoxic Payload and

mechanism of action

Linker DAR Phase of

developmentTisotumab vedotin (HuMax-

TF-ADC; TF011-MMAE)

(Seattle Genetics, Inc.)

Tissue factor

Fully human monoclonal

antibody

MMAE


Protease cleavable

valine-citrulline linker

Phase II ongoing;

Phase III in cervical

cancer ongoing

Anetumab ravtansine (BAY

94-9343)

(Bayer)

Mesothelin

Fully human IgG1 (MF-T)

Ravtansine/

DM4


Sulfo-PDB 3.2 Phase II ongoing

DMOT4039A (RG7600)

(Genentech, Inc.)

Mesothelin

Humanized IgG1 antibody

(h7D9.v3)

MMAE


Protease cleavable


3.5 Phase II

BMS-986148

(Bristol-Myers Squibb)

Mesothelin

Fully human IgG1 monoclonal

antibody

Duocarmycin-related

DNA alkylation

Protease cleavable


1.4 Phase I/IIa ongoing

Sofituzumab vedotin

(DMUC5754A)

(Genentech, Inc.)

MUC16

Humanized IgG1 monoclonal

antibody

MMAE


Protease cleavable


(maleimidocaproyl-

valine-citrulline-p-

aminobenzyloxycarbonyl)

3.5 Phase I completed;

further development

discontinued

Anti-MUC16 TDC

(DMUC4064A)

(Genentech, Inc.)

NCT02146313

MUC16

Humanized anti-MUC16 IgG1

MMAE


Cysteine-engineered

THIOMABTM

2 Phase I completed

Calo CA, O'Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer. Expert Opin Biol Ther. 2020 Jun 8:1-13. doi: 10.1080/14712598.2020.1776253. Online ahead of

print. PMID: 32463296

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Thank you

targeted approach using biomarkers, adc's the next frontier

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