Clinical Progress of Antibody-Drug Conjugates

 

Antibody-drug conjugates (ADCs) continue to emerge as a strong and promising strategy for target cancer therapy. Today, there are four ADCs approved and commercially available in the US, with another 175 investigational ADCs in development, from early discovery to clinical phase III trials, across both hematologic malignancies and solid tumor indications. Some of these trials are single-agent trials, while others are combinations. Companies are leveraging on lessons learned from first and second-generation trials to inform on next-generation ADC designs.

In this second installment of our 2-part ADC program, PEGS Boston’s 9th Annual Clinical Progress of Antibody-Drug Conjugates will invite investigators to share their latest results from preclinical and clinical trials, lessons learned to inform drug design & dosing, and strategies to improve safety, efficacy and patient outcomes.

Final Agenda

 

THURSDAY, APRIL 11

12:00 pm Registration (Commonwealth Hall)

12:35 Luncheon in the Exhibit Hall with Poster Viewing (Commonwealth Hall)

STRATEGIES TO INFORM DRUG DESIGN & DOSING, AND IMPROVE PATIENT OUTCOMES

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1:40 Chairperson’s Opening Remarks

Thomas Held, MBA, Vice President, ADC Task Force, Daiichi Sankyo

1:50 Single-Cell PK/PD of Antibody-Drug Conjugates and Immuno-Oncology Agents to Design More Effective Therapies

Thurber_GregGreg Thurber, PhD, Assistant Professor, Chemical Engineering and Biomedical Engineering, University of Michigan

Antibody-drug conjugates and checkpoint inhibitors are powerful agents in the treatment of cancer. However, the delivery and distribution of these agents in the tumor microenvironment is complex. We are using single-cell measurements within the tumor to inform better decisions on drug design and dosing.

2:20 Chemo-Enzymatic Glycan Conjugation of Toxic Payloads: Clinical-Stage GlycoConnect(TM) ADCs Demonstrate Superior Therapeutic Index

vanBerkel_SanderSander van Berkel, PhD, Director, R&D Operations, Synaffix B.V.

The native glycan of monoclonal antibodies is evolving as a privileged site to generate ADCs with a significantly improved therapeutic index, as corroborated by a multitude of studies in rodents and NHPs. While the first clinical studies with a GlycoConnect™ ADC are now underway (NCT03700294), we will discuss how mAb glycan structure correlates with therapeutic index, as well as aspects of CMC supply chain and regulatory considerations towards IND filing.

2:50 Developing Antibody-Drug Conjugates as Targeted Conditioning Agents for Bone Marrow Transplant

McDonagh_CharlotteCharlotte McDonagh, PhD, Vice President, Head, Biotherapeutics, Magenta Therapeutics

Many diseases can be cured by a bone marrow transplant. Prior to transplant, patients are conditioned by removing their own bone marrow stem cells using toxic, non-selective chemotherapy and radiation. Many patients suffer serious side effects, and others refuse a transplant. This presentation will highlight preclinical development of antibody-drug conjugates that may be safer, targeted agents for patient preparation with the aim of extending the use of curative bone marrow transplant and improving patient outcomes.

3:20 Development and Clinical Updates on Sacituzumab Govitecan

Iannone_RobertRobert Iannone, MD, MSCE, Head, R&D, CMO, Immunomedics

3:50 Networking Refreshment Break (Harbor & Mezzanine Level)

IMPROVING THE SAFTEY AND EFFICACY OF ADCs

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4:20 Preclinical Study of Liver Injury Induced by T-DM1: Molecular Mechanisms of T-DM1-Induced Hepatotoxicity

Wu_WenJinWen Jin Wu, MD, PhD, Senior Investigator, OBP, CDER, FDA

Hepatotoxicity is one of the serious adverse events associated with T-DM1. We show that T-DM1 is internalized upon binding to cell surface HER2, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. Based on our data, we propose that T-DM1-induced upregulation of TNFa enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. In addition, a novel target that mediates T-DM1-induced hepatotoxicity will also be discussed.

4:50 POSTER HIGHLIGHT:  Exploring the Ever-Evolving Bioanalytical Strategy for ADCs from Discovery to the Clinic

Tarcsa_EditEdit Tarcsa, PhD, Director, Drug Metabolism & Pharmacokinetics, AbbVie

ADCs are complex therapeutic modalities with the possibility of forming multiple analytes in vivo. A wide variety of assays and multiple analytical platforms had been utilized for their characterization. How do we chose what is appropriate to support decision making at the various stages of a project and how does one go by balancing speed, quality and available reagents. Since the key questions to answer during drug discovery (ADC optimization), versus late stage development are usually very different, therefore the analytes and assays appropriate to answer those questions could also be different. A few case studies and a bioanalytical decision tree will illustrate the issues.

5:20 End of Day

5:20 Registration for Dinner Short Courses (Commonwealth Hall)


Recommended Dinner Short Course*

SC12: Design Strategies and Development of ADCs

Robert Lutz, PhD, Principal Consultant, Crescendo Biopharma Consulting

 

*Separate registration required.

 

FRIDAY, APRIL 12

8:00 am Morning Coffee (Harbor Level)

8:30 Chairperson’s Remarks

Greg Thurber, PhD, Assistant Professor, Chemical Engineering and Biomedical Engineering, University of Michigan


8:35 KEYNOTE PRESENTATION: The House of Vedotins

Lechleider_RobertRobert J. Lechleider, MD, Senior Vice President, Clinical Development, Seattle Genetics

Antibody-drug conjugates have proven effective in treating an array of cancers. Among the most active drug-linker combinations is monomethyl-auristatin E (MMAE) coupled to a targeting antibody via a valine-citrulline linker. MMAE conjugates have shown activity in heme and solid tumors using a number of targeting antibodies. The role and future of MMAE drug conjugates in the treatment of cancer will be discussed.

PRECLINICAL UPDATES AND PROOF-OF-CONCEPT

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9:05 A Novel Antibody-Drug Conjugate Targeting ADAM9-Expressing Solid Tumors Demonstrates Potent Preclinical Activity

Hicks_StuartStuart Hicks, PhD, Director, Pipeline R&D, ImmunoGen

ADAM9 is a cell surface protein that belongs to the ADAM (a disintegrin and metalloproteinase) family of proteases and is overexpressed in multiple solid tumor indications. IMGC936 is a novel ADAM9-targeting ADC comprised of a high-affinity humanized antibody site-specifically conjugated to DM21, a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable peptide linker. IMGC936 shows compelling efficacy in ADAM9-positive xenograft models and was well-tolerated following repeat dosing in cynomolgus monkeys making IMGC936 a promising therapeutic candidate to target a wide range of ADAM9-expressing tumors.

   


9:35 CD163 as a Target for Directing ADCs to Macrophages in Cancer and Inflammation – Preclinical Proof of Concept

Graversen_JonasJonas Heilskov Graversen, PhD, Associate Professor, Molecular Medicine, University of Southern Denmark

We have validated the macrophage specific internalization receptor CD163 as an ADC target in cancer and inflammation. PoC studies in mice, rats and pigs show a strongly reduced (50-fold) effective dose for anti-inflammatory effect when targeting dexamethasone to macrophages (endotoxemia and NASH models). In cancer we observe substantially increased infiltration of effector T-cells and T-cell dependent tumor regression in a murine anti-PD-1 resistant melanoma model when eradicating tumor associated macrophages by toxin targeting.

10:05 Networking Coffee Break (Harbor & Mezzanine Level)

10:35 Amanitin-based Antibody-Drug Conjugates as New Therapeutic Modalities for Cancer Therapy

Badescu_GeorgeGeorge Badescu, PhD, VP, Scientific Affairs, Heidelberg Pharma

Antigen-targeted Amanitin-Conjugates (ATACs) represent a new class of ADCs using the payload Amanitin. This payload introduces a novel mode of action into oncology therapy, the inhibition of RNA polymerase II. The technology platform includes Amanitin supply, site-specific conjugation, demonstrated safety profile and biomarker. HDP-101 is the first ATAC directted against BCMA entering Phase I trials by end of 2019.

CLINICAL DEVELOPMENT AND LESSONS LEARNED

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11:05 Targeting Breast Cancer with Antibody-Drug Conjugates

Bardia_AdityaAditya Bardia, MD, MPH, Assistant Professor, Medicine, Harvard Medical School

Chemotherapy is the mainstay of management of multiple solid tumors, but can be associated with considerable adverse effects. Conceptually, antibody-drug conjugates can be utilized for targeted delivery of toxic payloads to cancer cells. However, antigen selection of antigen and tumor heterogeneity are significant challenges in clinical development of novel antibody-drug conjugates. In this presentation, we will review potential therapeutic strategies and the clinical development of antibody-drug conjugates in breast cancer.

11:35 Discovery of Next-Generation ADCs: Preclinical and Clinical Development of AVID100, an EGFR-Targeting ADC

O'Connor-McCourt_MaureenMaureen O’Connor-McCourt, PhD, CSO, Forbius

AVID100 is an EGFR-targeting ADC which was designed by screening a library of anti-EGFR ADCs against both tumor and normal cells expressing EGFR. This approach enabled us to identify AVID100, which exhibited a very promising therapeutic index in preclinical studies. AVID100 recently completed a successful phase 1 clinical program and a phase 2 study has been initiated. Importantly, only modest skin toxicity was observed, as predicted by our preclinical data.

12:05 pm [Fam-] Trastuzumab Deruxtecan (DS 8201) Clinical Development Update

Held_ThomasThomas Held, MBA, Vice President, ADC Task Force, Daiichi Sankyo


12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:05 Networking Refreshment Break (Harbor & Mezzanine Level)

1:35 Chairperson’s Remarks

Maureen O’Connor-McCourt, PhD, CSO, Forbius

NEXT-GENERATION ADCs

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1:40 Next-Generation ADCs: Considerations and Examples

Damelin_MarcMarc Damelin, PhD, Executive Director, Head of Biology, Mersana Therapeutics, Inc.

I will discuss considerations for the discovery and development of next-generation ADCs as informed by learnings from the field's collective experience. Topics will include target selection, molecular design, and preclinical pharmacology.

2:10 Targeting CD74 with a Novel Antibody-Drug Conjugate, STRO-001 for Treatment of B-Cell Malignancies

Molina_ArturoArturo Molina, MD, MS, FACP, CMO, Sutro Biopharma

 

 

 

2:40 Antibody-Drug Conjugates Targeting Tumor Stromal Cells

St_Croix_BradBrad St. Croix, PhD, Head, Tumor Angiogenesis Unit, Mouse Cancer Genetics Program, National Cancer Institute

Targeting the tumor stromal cells in addition to tumor cells with ADCs is a promising anti-cancer strategy. CD276 and TEM8 are variably expressed in a variety of cancers and to different extents on tumor stromal cells and tumor cells. Both CD276-ADC-PBD and TEM8-ADC-MMAE eradicated large established tumors and metastases and improved long-term overall survival in several different mouse models of cancer. The mechanistic basis for the efficacy of these agents will be discussed, along with implications for other vascular-targeted ADCs.

3:10 Tisotumab Vedotin – A Novel Tissue Factor-Targeting Antibody-Drug Conjugate for the Treatment of Advanced Solid Tumors

Harris_JeffreyJeffrey Harris, PhD, Associate Director, Translational Research, Genmab

Tisotumab vedotin (TV) is an antibody-drug conjugate (ADC) that binds and interferes with tissue factor signaling, has potent anti-tumor activity in vitro and in vivo, and minimal effect on pro-coagulant activity. TV is efficiently internalized to the lysosome of the cell, making it an optimal ADC. TV is currently being tested in multiple clinical trials evaluating the safety, tolerability, and anti-tumor activity in patients with previously treated and advanced metastatic solid tumors.

3:40 End of Conference

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