Cambridge Healthtech Institute’s 3rd Annual
Antibody-Drug Conjugates
Engineering for Clinical Success
January 19-20, 2016

KEYNOTE PRESENTATION

2:05 Antibody Drug Conjugates – Past, Present and Future

Peter Senter, Ph.D., Vice President, Chemistry, Seattle Genetics, Inc.

With more than 30 ADCs in clinical testing and 2 FDA-approved products, ADCs have the potential to be a significant part of the cancer therapy armamentarium. This talk will review the history of ADCs, emerging clinical data with existing ADCs and future innovations designed to enhance clinical activity of ADCs.

ADCs IN THE CLINIC

4:00 Use of Physiologically-Based Pharmacokinetic (PBPK) Modeling to Assess Drug Interaction Potential of Antibody-Drug Conjugates (ADCs)
Divya Samineni, Ph.D., Clinical Pharmacologist, Antibody Drug Conjugates, Genentech, Inc., a member of the Roche Group 
Monomethyl auristatin E (MMAE, a cytotoxic agent), upon releasing from valine-citrulline-MMAE (vc-MMAE) antibody-drug conjugates (ADCs), is expected to behave like small molecules. Therefore, evaluating the drug–drug interaction (DDI) potential associated with MMAE is important in the clinical development of ADCs. A PBPK model linking antibody-conjugated MMAE (acMMAE) to its catabolite unconjugated MMAE associated with vc-MMAE ADCs developed using a mixed ‘bottom-up’ and ‘top-down’ approach will be discussed.

4:30 Molecular Integrity of Antibody-Drug Conjugates: Applying Preclinical Learnings to the Clinic

Brooke Rock, Ph.D., Senior Scientist, Pharmacokinetics and Drug Metabolism, Amgen, Inc.

Characterizing the mechanisms of ADC instability and release of the cytotoxin are germane in the design of the next generation of ADCs. The metabolism and disposition of ADCs, especially in regards to non-cleavable cytotoxins, are not fully understood. Understanding the mechanism behind release of the cytotoxin moiety and the chemistry that influences this release is important in both the efficacy of the ADC as well as toxicity profile.

5:00 The Role of Brentuximab Vedotin in Treatment of Hodgkin Lymphoma and in Prevention of Relapse Post High-Dose Therapy and Autologous Stem Cell Transplant

Auayporn P. Nademanee, M.D., Jan & Mace Siegel Professor, Hematology & Hematopoietic Cell Transplantation, Associate Clinical Director, Hematology & Hematopoietic Cell Transplantation, and Director, Matched Unrelated Donor (MUD) Program, City of Hope

Brentuximab vedotin (BV) consists of an anti-CD 30 antibody conjugated by a protease-cleavable linker to microtubule-disrupting agent, monomethyl auristatin E. In a pivotal Phase II trial, BV induced 75% response rate, 34% complete remission rate in patients with Hodgkin lymphoma (HL) who had relapsed after high-dose therapy and autologous stem cell transplant (Auto-SCT). The results show that giving BV post auto-SCT improved PFS in patients who were at risk for relapse.

WEDNESDAY, JANUARY 20

8:00 am Conference Registration and Morning Coffee

ENGINEERING ADCs

8:30 Chairperson’s Remarks

Mary J. Hinrichs, Ph.D., Principal Toxicologist, Biologics Safety Assessment, MedImmune

8:35 Impact of Disulfide Linker Variation on Antibody-Drug Conjugate in vitro and in vivo Properties

Peter Dragovich, Ph.D., Principal Scientist, Medicinal Chemistry, Genentech, Inc., a member of the Roche Group

ADCs are a growing class of anti-cancer therapeutic agents that are comprised of an antibody attached to a cytotoxic payload via a linking moiety. We previously disclosed the design of a new ADC linker that is directly attached to a mAb cysteine residue via a disulfide bond. Several structural modifications of this disulfide linker will be described along with the associated impacts on ADC cell-culture potency, pharmacokinetics, and xenograft efficacy.

9:05 The Application of Site-Specific Conjugation Technology to Create Novel Bispecifics, Pegylated Biologics and Peptide Conjugates

Aaron K. Sato, Ph.D., Vice President, Research, Sutro Biopharma, Inc.

Using Xpress CF+, hundreds of non-natural amino acid antibody variants are made within a day. Using fast, quantitative conjugation chemistries, e.g. Click Chemistry, antibodies are conjugated within hours. The variants are selected based on expression, cell binding, conjugation efficiency, and cell killing. This technology has also been applied to other therapeutic modalities, e.g. peptides and proteins. Case studies will be presented in this talk.

9:35 An Integrated Approach to Managing Immunogenicity Risk and Drug Immune Modulation

Jeremy Fry, D.Phil., Director, Sales, ProImmune

Immunogenicity is one of the most complex issues to address in drug design and development. I will provide an overview of the best tools to mitigate immunogenicity risk, including Mass Spectrometry antigen presentation assays; DC-T and T cell proliferation assays for biologic lead selection/optimization; HLA-peptide binding assays to characterize individual epitopes as well as undiluted whole blood cytokine storm assays.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing

10:50 Strategies to Generate Stable and Homogenous ADCs

Changshou Gao, Ph.D., Fellow, R&D, Antibody Discovery & Protein Engineering, MedImmune LLc

Various conjugation approaches have been developed to generate homogenous ADCs with well-defined drug to antibody ratios. However, the stability of ADCs plays a critical role in the activity and potency of the ADCs. This presentation will use case studies to discuss our recent effort to generate stable ADCs with different conjugation chemistries that allow precise control of conjugation site and stoichiometry for enhanced stability, increased in vivo efficacy, and decreased off-target toxicity.

11:20 Sweet Delivery of the Bitter – Using Carbohydrate-Targeting Antibodies for Tumor-Specific Delivery of Cytotoxic Drugs

Felix Hart, MSc, Scientist, Bioassays & Nonclinical Studies, Glycotope GmbH

ADCs have great potential to deliver cytotoxic agents to cancer cells. For three novel glyco-optimized antibodies, carbohydrates on the surface of cancer cells represent promising targets for the specific delivery of cytotoxic drugs for cancer therapy. Tumor specificity and Fc-mediated effector functions were shown by immunohistochemistry and antibody-dependent cellular cytotoxicity, respectively. Next, as a prerequisite for intracellular drug delivery, target internalization upon antibody binding and lysosomal localization were confirmed.
>>> View a recent interview

11:50 Innovative Payload Platform Powers ADC Development

Ravi J. Chari, Ph.D., Vice President, Chemistry & Biochemistry, ImmunoGen, Inc.
A majority of ADCs currently in clinical trials use a tubulin interacting agent (maytansinoids or auristatins) as the payload. There is considerable interest in developing payloads with alternative mechanisms of cell killing. The key requirements and challenges for payload development for ADCs will be discussed. The design of ImmunoGen’s novel payload platform, along with preclinical data that support their further advancement will be highlighted.

12:20 pm Linkers with High Drug Loads and Precisely Controlled Chemical Structure based on XTEN™

Volker Schellenberger, Ph.D., President and CEO, Amunix

Since 2006, Amunix has been developing precision engineered protein polymers trademarked as XTEN™for use in half-life extension and drug delivery. Precisely customized, highly soluble XTEN structures can be produced in large quantities over a wide size range (5 to >100kDa) and with precisely controlled drug conjugation sites. XTEN can provide half-life in addition to its action as a drug linker. This allows the utilization of peptides and antibody fragments in addition to IgGs for tumor targeting.

12:50  Session Break

1:00  Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

CONQUERING CANCER WITH ADCs

2:00  Chairperson’s Remarks

Peter Dragovich, Ph.D., Principal Scientist, Medicinal Chemistry, Genentech, Inc., a member of the Roche Group

2:05  Development of Next-Generation Antibody-Drug Conjugates

Feng Tian, Ph.D., Chief Scientific Officer, Ambrx, Inc.

2:35  ADCs Targeting Embryonic and Pluripotent Stem Cell Markers as Novel Therapeutics for Metastatic Cancers

Michael Schopperle, Ph.D., CEO, CureMeta

New research suggests that metastatic and aggressive cancers may be caused by reprogrammed cancer stem cells with embryonic and pluripotent characteristics. We have developed several antibodies which are specific for embryonic stem cells markers and have made several ADCs as novel therapeutics for metastatic cancers. Our studies show that our new ADCs are specific for and highly efficient at killing pluripotent cancer stem cells.

3:05  XMT-1522: A Novel Anti-HER2 ADC for the Treatment of Low HER2-Expressing Tumors and Combination with Trastuzumab-Based Regimens in HER2-Driven Tumors
Natasha Bodyak, Ph.D., Senior Director, Biology, Mersana Therapeutics, Inc.

There is a need for more potent anti-HER2 ADCs to maximize benefits. XMT-1522 is an anti-HER2 ADC that uses a novel, human anti-HER2 antibody optimized for cytotoxic payload delivery, and is non-competitive with trastuzumab or pertuzumab for HER2 binding. This presentation will highlight pre-clinical data demonstrating potent anti-tumor activities of XMT-1522 as a single agent in low HER2-expressing tumors and in combination with trastuzumab and pertuzumab in HER2-driven tumors.

3:35  Refreshment Break in the Exhibit Hall with Poster Viewing

INNOVATIVE ENGINEERING

4:30 Probody Therapeutics and the Target Landscape for Drug Conjugates

Luc R. Desnoyers, Ph.D., Director, Oncology, CytomX Therapeutics, Inc.

CytomX’s Probody Drug Conjugates (PDC) Platform is a novel and differentiated approach for developing highly targeted antibody therapeutics. Probodies are designed to expand the therapeutic window by focusing antibody efficacy directly to diseased tissues. PDCs are activated selectively in the TME, leading to improved PK and toxicity profiles. PDCs can target proteins not suitable for ADC development. In vivo efficacy and safety studies demonstrate an improved therapeutic index.

5:00 Site-Specific ADCs of Un-Modified Antibodies: Production and in vivo Stability, Efficacy, and Toxicity

Sean Hu, Ph.D., Senior Vice President, R&D, Dophen Biomed

Site-Specific ADCs are made in a one-pot reaction directly from un-modified mABs using engineered transglutaminase. Such ADCs are as stable as their parent mABs in blood circulation with toxins remaining 100% attached for 21 days after injection. They are 4 to 8 times more efficacious in xenograft models than their counterparts of random conjugation via lysine residues. This platform works directly for any intact IgG1, IgG2, or IgG4.

6:30-7:30 Reception in the Exhibit Hall with Poster Viewing

7:30 Close of Conference