Lessons learned from the two marketed ADCs and the ongoing ADC trials have not only enabled scientists to better understand the mechanisms of action of antibody-drug conjugates, but also helped invigorate a new field of ADC study aimed at overcoming the challenges of poor internalization, tumor non-specificity, off-target toxicity, lack of efficacy, low expression levels and multi-drug resistance. Today, scientists continue to innovate on next generation ADCs by improving target selection, finding new cytotoxic drugs as warheads, engineering antibodies or discovering alternative effector moieties to increase half-lives and improve target specificity, optimizing linker-payload chemistry to produce stable and homogeneous ADCs, and overcoming the challenges of multi-drug resistance.
The Antibody-Drug Conjugates I: New Targets, Payloads and Alternative Formats conference will present scientists’ creativity in the design and optimization of next-generation bioconjugates.
Final Agenda
Recommended Short Courses*
SC9: Target Selection for Biologics - Detailed Agenda
SC15: Critical Considerations for the Design and Development of Antibody-Drug Conjugates - Detailed Agenda
*Separate registration required
WEDNESDAY, MAY 3
7:30 am Registration and Morning Coffee
8:30 Chairperson’s Remarks
Ravi Chari, Ph.D., Vice President, Chemistry & Biochemistry, ImmunoGen, Inc.
8:40 BT1718, A Bicycle Drug Conjugate (BDC) Targeting MT1-MMP for Treatment of Solid Tumors
Peter Park, Ph.D., Vice President, Oncology Research, Bicycle Therapeutics
The Bicycle® platform allows hugely diverse libraries of constrained, bicyclic peptides (Bicycles®), generated with a chemical scaffold, to be displayed on the surface of viable bacteriophage. Their relatively small size (1.5-2 kDa) delivers advantages in tumor penetration and extravasation and the fast, renal clearance avoids liver and GI toxicity often associated with other drug modalities. This presentation will exemplify the Bicycle platform and describe the discovery and development of BT1718, a potent Bicycle Drug Conjugate targeting MT1-MMP.
9:10 Abdurin-Drug Conjugates: A New Generation of Targeted Therapeutics
Kurt Gehlsen, Ph.D., Vice President and CSO, Therapeutics, Research Corporation Technologies, Inc.
Abdurins are a small antibody-like scaffold that retains a long circulating half-life. Abdurins are amenable to high-throughput screening to isolate binders to targets of interest. Abdurins have demonstrated improved tumor penetration compared to a monoclonal antibody and have been conjugated to MMAE and a deimmunized ribotoxin, SarcinDI. The smaller size and longer half-life of Abdurins may facilitate enhanced payload delivery to solid tumors compared to standard antibody-drug conjugates.
9:40 Small is Beautiful – Humabodies Drug Conjugates, HDCs a Real Alternative to ADCs
Thomas Sandal, Ph.D., Vice President, R&D, Crescendo Biologics Ltd.
- HDCs demonstrate exceptionally fast tumour penetration
- HDCs facilitate low systemic exposure
- Humabodies enable plug and play engineering allowing simple exploration of limitless format options
- The versatility of the Humabody™ platform enables creation of optimal HDC format and half-life with improved Therapeutic Index
10:10 Coffee Break in the Exhibit Hall with Poster Viewing
10:55 HDP-101 – A BCMA-Targeted Amanitin-Based ADC
Andreas Pahl, Ph.D., CSO, 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 around ATACs includes Amanitin supply, site-specific conjugation, demonstrated safety profile and biomarker. A BCMA-ATAC has been selected based on favorable preclinical data to start the clinical development of the first ATAC.
11:25 Development of Potent and Selective Antibody-Drug Conjugates Targeting Different Antigens with Pyrrole-Based KSP Inhibitors as Novel Payload Class
Hans-Georg Lerchen, Ph.D., Principal Scientist, Drug Discovery, MedChem, Bayer AG
The identification of ADC payload classes with a novel mode of action will increase therapeutic options and potentially help to overcome resistance. Small molecule inhibitors of kinesin spindle protein (KSP/Eg5) have generated interest due to their high antitumor potency. A new pyrrole subclass of KSP inhibitors with sub-nanomolar potency against a large panel of tumor cell lines has been established as a versatile new payload class for the generation of potent and selective ADCs against different targets.
11:55 Expanding the Therapeutic Window of ADCs with Zymelink™ Novel Linkers and Payloads
John Babcook, Ph.D., Senior Vice President, Discovery Research, Zymeworks Inc.
ZymelinkTM is a novel drug-conjugate platform consisting of a modular suite of proprietary payloads, linkers and site-specific conjugation technologies designed for the targeted delivery of therapeutics with optimal efficacy and safety profiles. It is compatible with traditional monoclonal antibodies, AzymetricTM (bispecific) and AlbuCORETM (multispecific) platforms for the development of next-generation biotherapeutics.
12:25 pm Latest Advances Developing ADCs using SMARTag™ Technology
David Rabuka, Ph.D., Global Head of Research & Development, Chemical Biology, Biologics Research & Development, Catalent Pharma Solutions
We have developed the SMARTag™ technology platform, which enables precise, programmable, site-selective chemical protein modification. Leveraging the target sequence of Formylglycine Generating Enzyme (FGE) we chemoenzymatically modify proteins to generate a precisely placed aldehyde functionality that can be chemically elaborated. We will present our novel protein modification platform and its application to generating ADCs, including our new conjugation chemistries and linkers.
12:55 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:55 Session Break
2:10 Chairperson’s Remarks
Peter Park, Ph.D., Vice President, Oncology Research, Bicycle Therapeutics
2:15 KEYNOTE PRESENTATION: Antibody Drug Conjugates with Novel DNA Alkylating Agents: Design and Preclinical Evaluation
Ravi J. Chari, Ph.D., Vice President, Chemistry & Biochemistry, ImmunoGen, Inc.
There are currently over 50 Antibody-Drug Conjugates (ADCs) in clinical development, reflecting the growing interest in ADCs for the treatment of cancer. As part of our effort to expand the available toolbox of cytotoxic payloads, we have designed a new class of potent DNA-alkylating agents, “indolino-benzodiazepine dimers” (termed IGNs). The chemical design and preclinical data for representative IGN ADCs will be discussed.
2:45 KEYNOTE PRESENTATION: Novel DNA-Targeting Payloads for ADCs
Puja Sapra, Ph.D., Vice President and CSO, Target Therapeutics Unit, Oncology Research & Development, Pfizer, Inc.
We will review the development of Mylotarg & Inotozumab Ozogamicin. This talk will explore the next generation of Pfizer DNA-damaging ADCs
3:15 Poster Spotlight I: Fully Synthetic Trioxacarcin Analogs for Use in Antibody-Drug Conjugates
Ethan Magno, Sc.B., Graduate Student, Chemistry and Chemical Biology, The Myers Lab, Harvard University
3:30 Poster Spotlight II: Stable and Potent Selenomab-Drug Conjugates
Xiuling Li, Ph.D., Research Associate, Immunology and Microbiology, The Scripps Research Institute
3:45 Refreshment Break in the Exhibit Hall with Poster Viewing
4:45 Problem-Solving Breakout Discussions
These interactive discussion groups are open to all attendees, speakers, sponsors, & exhibitors. Participants choose a specific breakout discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion. Pre-registration to sign up for one of the topics will occur a week or two prior to the Event via the App.
Current Limitations of Targeted Therapies
Kurt Gehlsen, Ph.D., Vice President and CSO, Therapeutics, Research Corporation Technologies, Inc.
- How can we improve antibody-drug conjugates?
- What are the limitations of immunotoxins?
- Do bispecific antibodies improve the specificity of ADCs?
- What ADC warhead physiochemical properties are needed to improve ADC performance?
Bioanalytical Approaches to Antibody-Drug Conjugates
Rafiq Islam, MSc., Senior Director, Bioanalytical Services, Celerion, Inc.
- Which ADC analytes should be measured?
- Which ADC analytes are relevant to understanding exposure response relationship?
- What are preferred bioanalytical methods and technologies for the measurement of ADCs in clinical samples?
- What are the advantages and disadvantages of ligand binding methods and LC-MS/MS methods?
- How a hybrid LBA/ LC-MS/MS method can be implemented to successfully measure ADCs in biological smaples?
New Paradigms in Pre-Clinical Pharmacology to Guide Optimal Drug Discovery and Patient Selection Strategies for ADCs
Carl Uli Bialucha, Ph.D., Director, Oncology Biotherapeutics, Novartis Institutes for Biomedical Research, Inc.
- Translatability of xenograft efficacy to clinical activity – can better models and study design bridge gaps?
- The role of the immune system and tumor microenvironment in shaping therapeutic responses to ADCs – what can syngeneic models teach us?
Beyond ADC’s: Next-Generation Protein and Peptide Drug Conjugates
Joanna Hay, Ph.D., Science Manager, Customer Solution, Albumedix Ltd.
Advances in recombinant DNA, linker design and coupling chemistries offer the potential to prepare and test complex molecules. Several protein and peptide drug conjugates are now moving into clinical development and practice.
- What opportunities beyond that of ADC’s do protein and peptide conjugates offer?
- Advantages and disadvantages of peptide and protein drug conjugates as novel therapeutic approaches.
- Clinical and manufacturing challenges of protein and peptide drug conjugates.
5:45 Networking Reception in the Exhibit Hall with Poster Viewing
7:00 End of Day
THURSDAY, MAY 4
8:00 am Morning Coffee
8:30 Chairperson’s Remarks
Vijay Chudasama, Ph.D., Lecturer, Organic Chemistry and Chemical Biology, University College London
8:35 Elimination of Multidrug-Resistant Melanoma by Humax-AXL MMAE
David Satijn, Ph.D., Director, New Antibody Products, Genmab
- AXL is overexpressed in many types of cancer, including melanoma, and is associated with EMT and increased invasiveness of tumors.
- AXL is also upregulated upon resistance to a variety of therapies including the oft-used BRAF and MEK inhibitors in melanoma
- HuMax-AXL-MMAE shows efficacy in AXL-expressing melanoma CDX and PDX models
9:05 Herceptin® (Trastuzumab, Tz) with Covalent Attached Redox Selenium is More Cytotoxic to Tz Resistant JIMT-1 Breast Cancer Cells than Tz Alone by Generating Intracellular Superoxide and H2O2
Julian Spallholz, Ph.D., Professor, Nutritional Biochemistry, Nutritional Sciences, Texas Tech University
Herceptin® (Trastuzumab, Tz) treated women with Her/2 + breast cancer (BC) often relapse with their cancer becoming Herceptin resistant. To overcome resistance, an ADC, antibody-drug conjugate, Kadcyla® (ado-trastuzumab emtansine) was developed by Genentech. We replace Emtansine with a small redox selenium moiety (Mab-SeCN) that redox cycles and increases intracellular BC oxidative stress. The Se-Herceptin® ADC is more cytotoxic to Herceptin® resistant and Kadcyla® treated Herceptin® resistant JIMT-1 BC cells.
9:35 RESPECT (REsidue-SPEcific Conjugation Technology): A Platform Technology Utilizing Native Cysteine and Lysine Residues for the Generation of Homogeneous Antibody-Drug Conjugates
Jared Spidel, Ph.D., Principal Scientist, Antibody Core, Morphotek, Inc.
Our cysteine-specific conjugation method exploits a unique intrachain disulfide bond in the light chain of rabbit antibodies between cysteine residues at 80 and 171 of the variable and constant domains. Our humanization strategy allows retention of the C80 with a free thiol group that is amenable for residue-specific conjugation. Our C-terminal lysine-specific linkage method employs the transglutaminase enzyme catalyzing formation of an isopeptide bond between the IgG C-terminal K447 and a variety of glutamine-based payloads. ADCs prepared using our RESPECT technology produced uniform drug-to-antibody ratios and were shown to be highly potent and specific in vitro and in vivo.
10:05 Coffee Break in the Exhibit Hall with Poster Viewing
11:05 Site Selective Antibody Drug Conjugates Enabled by Cysteine Arylation
Bradley L. Pentelute, Ph.D., Professor, Chemistry, Massachusetts Institute of Technology
Here we report a robust bioconjugation method using cysteine arylation. This chemistry enables site-specific conjugation at cysteine residues within peptides, proteins, and antibodies. Our two developed approaches use either perfluoroaryl-cysteine SNAr chemistry or organometallic palladium reagents. Recently, we discovered a self-labeling four-residue sequence that enables regioselective conjugation at only one cysteine residue within an intact antibody containing natural amino acids.
11:35 Novel Lysosoma Cleavage Linker Leads to Potent and Stable Duocarmycin Conjugates
Ying Sun, Ph.D., Associate Director of Chemistry, Ambrx
Duocarmycin is very potent DNA alkylating agent. Duocarmycin as small molecule in the clinical trial was not successful due to the toxicity. Duocarmycin as payload for antibody drug conjugates has been explored by several companies. But the linker design for duocarmycin has been challenging. Here, we report a new linker design with novel lysosomal cleavage mechanism, which leads to potent and stable duocarmycin conjugates.
12:05 pm Fine-Tuning Functional Disulfide Re-Bridging to Enable the Formation of Homogeneous Antibody Conjugates and Exploring Novel ADC Avenues
Vijay Chudasama, Ph.D., Lecturer, Organic Chemistry and Chemical Biology, University College London
Our latest data on next generation maleimide and pyridazinedione reagents for the site-selective modification of antibodies will be detailed (robust serum stability, in vitro selectivity, in vivo efficacy, and an update our first-in-class reagents that effect both disulfide reduction and functional re-bridging). Also presented, will be how we have been able to use our platforms to create bispecifics, and a novel strategy for making DAR 2 constructs from a native antibody scaffold.
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12:35 End of Antibody-Drug Conjugates I: New Targets, Payloads and Alternative Formats