The complexity of antibody-drug conjugates with its many moving parts makes this field incredibly challenging yet full of potential for innovation. From novel targeting ligands to new conjugation methods, from multiple payloads to changing the drug-antibody
ratio, all these are challenging the convention for the design and development of next-generation ADCs. At Antibody-Drug Conjugates I: New Ligands, Payloads and Alternative Formats, we invite scientists to present their new technologies
and showcase how they are redefining the rules in the field of ADCs.
Continue your exploration of the antibody-drug conjugates field by attending the accompanying meeting, Antibody-Drug Conjugates II: Advancing toward the Clinic on April 28-29.
WEDNESDAY, APRIL 27
7:00 am Registration and Morning Coffee
8:00 Chairperson’s Remarks
Christopher D. Thanos, Ph.D., Senior Director, Biotherapeutics Discovery, Halozyme Therapeutics, Inc.
8:10 KEYNOTE PRESENTATION:
Determination of Cellular Processing Rates Points to Key Parameters for Antibody-Drug Conjugate Design
K. Dane Wittrup, Ph.D., C.P. Dubbs Professor, Chemical Engineering & Biological Engineering, Associate
Director, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Numerous processing steps occur before the active drug component of an ADC can reach its intracellular target. Increased understanding of ADC cellular processing may facilitate more rational design of ADCs. In this work, we present a generalizable
method to determine kinetic parameters, which can be used in a basic model for cellular processing of ADCs and can be incorporated into larger scale pharmacokinetic/pharmacodynamic models.
8:40 KEYNOTE PRESENTATION:
Combining Antibody-Drug Conjugates and Immune-Mediated Cancer Therapy: What to Expect?
Hans-Peter Gerber, Ph.D., Vice President, CSO, Bioconjugates Discovery & Development, Oncology
Research Unit East, Pfizer Worldwide Research & Development
Toxins targeting DNA like anthracyclines or tubulin poisons like vinblastine can stimulate the innate immune system. When combined immuno-oncology (IO) compounds, both classes of toxins further enhanced the adaptive immune response and improved
the anti-tumor responses. Therefore, identification of optimal combination regimens between ADCs employing different classes of toxins and IO compounds holds strong promise to overcome the key limitations of current immune checkpoint inhibitors,
by increasing the recruitment and infiltration of CD8+ effector T cells to the tumor.
9:10 Small Ligand-Targeted Drug Conjugates: An Alternative to ADCs
Philip S. Low, Ph.D., Director of the Purdue Center for Drug Discovery, Ralph C. Corley Distinguished Professor, Department
of Chemistry, Purdue University
We have developed small molecule ligands for use in targeting attached drugs to pathologic cells, thereby avoiding collateral toxicity to healthy cells. We have also developed low molecular weight targeting ligands to deliver attached drugs selectively
to cancers that over-express PSMA, CCK2 receptor, neurokinin 1 receptor, carbonic anhydrase IX , and several other tumor-specific receptors. Finally, ligand-targeted imaging and therapeutic agents for autoimmune, inflammatory, and infectious diseases
(e.g. malaria, rheumatoid arthritis, multiple sclerosis, psoriasis, atherosclerosis, osteoarthritis, etc.) will also be described.
9:40 Targeted Protein Therapeutics (TPTs) for the Treatment of Cancer
Greg Adams, Ph.D., Chief Development Officer, Viventia Biotech
TPTs are fully biologic constructs containing antibody fragments and protein toxin payloads in a single engineered molecule. The preclinical/clinical development of TPTs employing fully deimmunized payloads for the treatment of systemic disease and non-deimmunized
payloads for use in the treatment of loco regional disease will be discussed.
10:10 Coffee Break in the Exhibit Hall with Poster Viewing
10:55 Development of Probody-Drug Conjugates Targeting Highly Expressed Tumor Antigens
Luc Desnoyers, Ph.D., Director, Oncology, CytomX Therapeutics, Inc.
PDCs are antibody prodrugs that are designed to be activated in tumors while avoiding binding to normal tissues. PDCs can safely enable targeting of antigens with broad, persistent & very high expression in cancer that are also expressed in normal
tissues, and therefore cannot be approached with traditional Antibody-Drug Conjugates. Such targets can show >70% prevalence at 3+ expression in many cancer types. Preclinical proof of concept for safety, efficacy & developability of PDCs to
high expression targets will be shown.
11:25 Immunomodulation by CO Delivered from Artificial Metalloproteins
Goncalo J.L. Bernardes, Ph.D., Group Leader, Chemistry, University of Cambridge
A new class of therapeutic metalloproteins allows for the controlled and targeted delivery of carbon monoxide (CO) into tumors. When administered into tumor bearing mice, the CO-releasing metalloproteins result in strong tumor growth retardation. The
CO-mediated effect is due to the combined downregulation of important angiogenic factors as well as activation of CD8 cytotoxic T cells. Finally, when used in combination with current standard of care chemotherapeutic drugs, the novel CO immune-modulation
treatment results in cancer cures in mice.
11:55 Drug Conjugation and Delivery Enabled by a Tumor-Targeting Peptide-Fc Fusion
Jennifer Cochran, Ph.D., Associate Professor, Bioengineering, Stanford University
We are creating novel peptide-drug conjugates for targeted delivery of chemotherapeutic agents to tumors. As an example, an integrin targeted peptide-Fc fusion, conjugated to an auristatin derivative, was effective as a single agent at inducing regression
and prolonged survival in tumor xenograft models. These studies provide proof-of-concept for further development of peptide-drug conjugates as attractive alternatives to ADCs for tumor targeting and drug delivery applications.
12:25pm Selected Poster Presentation:
Recent Advances in Chemistry & Biology of Protein Drug Conjugates (PDC)
Daniel Custar, Ph.D., Scientist, Oncology, Eisai Inc.
Preclinical work around a novel peptide drug conjugate (PDC) will be disclosed. The syntheses of a suitable cytotoxic warhead, along with linker development, and conjugation to a novel peptide will be outlined. Finally the in vitro stability
and in vivo efficacy and PK data will be presented.
12:55 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on your Own
1:55 Session Break
2:10 Chairperson’s Remarks
Hans-Peter Gerber, Ph.D., Vice President and CSO, Bioconjugates Discovery & Development, Oncology Research Unit East, Pfizer Worldwide R&D
2:15 Development of a Novel Protease Cleavable Linker for Anti-Staphylococcus Aureus Antibody-Antibiotic Conjugates
Martine Darwish, Senior Scientific Researcher, Protein Chemistry, Genentech
Antibody-Antibiotic Conjugates (AACs) employ an antibody specific for cell wall components of Staphylococcus aureus conjugated with a potent antibiotic. We describe the development of a peptide linker that is cleaved by staphopain B, a secreted
endopeptidase of S. aureus. The resultant AAC has demonstrated efficacy in in vitro and in vivo models of MRSA infection, providing a novel mechanism by which to target MRSA infections and release payload in a disease specific
2:45 MM302, A Novel Antibody-Drug Conjugated Liposomal Doxorubicin That Specifically Her2-Overexpressing Cancer Cells
Istvan Molnar, MD., Vice President, Clinical Development, Merrimack Pharmaceuticals
Despite improvements in treatment, HER2-positive metastatic breast cancer remains a life-threatening disease. MM-302 is a HER2-targeted PEGylated liposome that encapsulates doxorubicin to facilitate its specific delivery to HER2-overexpressing tumors.
Preclinical studies revealed synergistic antitumor activity for MM-302 in combination with trastuzumab. Phase 1 clinical investigation showed an acceptable safety profile and indicated promising clinical activity. MM-302 is currently under investigation
in a randomized phase 2 clinical trial (HERMIONE).
3:15 Developing Site-Specifically Modified ADCs Using a Chemoenzymatic Approach
David Rabuka, Global Head, Research & Development, Chemical Biology, Catalent Pharma Solutions
Antibody-drug conjugates (ADCs) have become de rigueur for pharmaceutical oncology drug development pipelines. We have developed the SMARTagTM technology platform, which enables precise, programmable, site-selective chemical protein modification. We will
highlight progress in developing these SMARTagTM ADCs with a focus on preclinical studies as well as highlight our progress in cell line development and manufacturing of bioconjugates using this chemoenzymatic approach.
3:45 Refreshment Break in the Exhibit Hall with Poster Viewing
4:45 Problem-Solving Breakout Discussions
- The pros and cons of large and small molecular weight ligand-targeted drug conjugates
Philip S. Low, Ph.D., Director of the Purdue Center for Drug Discovery, Ralph C. Corley Distinguished Professor, Department of Chemistry, Purdue University
- The large size of ADCs assures a large AUC but limits tumor penetration. Which property is most important for therapeutic efficacy? Is there an optimal ligand size that yields the best AUC and tumor penetration?
- Is AUC important when the number of targeted receptors is limited? How does receptor recycling rate impact this answer?
- Is there a relationship between targeted receptor number and the potency of the targeted cytotoxic drug required for therapeutic efficacy?
- How can one design a linker in a ligand-targeted drug conjugate that is stable in circulation and cleavable upon endocytosis into the diseased cell?
- ADCs : Past, Present and Future
Peter Hofland, Ph.D., Managing Partner, Publisher and Executive Editor, ADC Review
Coining the turn ‘magic bullet; the German physician and
scientist Paul Ehrlich proposed, more than a century ago, the concept of
selectively delivering a cytotoxic drug to a tumor via a targeting
agent. Ehrlich’s concept of targeted therapy was first exemplified
when methotrexate (MTX) was linked to an antibody targeting leukemia
cells. In 1975, the landmark development of mouse mAbs using
hybridoma technology by Kohler and Milstein greatly advanced the field of
ADC. The first ‘real’ ADC, gemtuzumab ozogamicin (Mylotarg) was
approved in 2000. However, despite initially encouraging clinical
resuls, the drug was withdrawn from the market in 2010 owing to a lack of
improvement in overall survival.
Today there are two approved ADC: brentuximab vedotin (Adcetris;
Seattle Genetics) and ado-trastuzumab emtansine (Kadcyla;
Genentech/Roche). With nearly 50 in clinical trials, and an average
clinical development time of ~6 years for ADCs, the expectation
is that in the next 3 – 4 years the number of new, approved,
ADCs will increase dramatically. But what are some of the hurdles to
be expected in bringing novel ADCs to the clinic? ADCs
in clinical development are directed against a range of
different antigenic targets. However, there is a limited number of
cytotoxic drugs, including calicheamicin, auristatins, maytansinoids,
duocarmycins and pyrolidobenzodiazepines (PBDs) confirming
the difficulties of finding fitting cytotoxic drugs as payloads in
ADCs. How do these highly potent agents support an average of
drug-to-antibody ratio (DAR) of 2 to 4? Are they not too hydrophobic? Are
they linkable? Are they accessible by simple synthetic pathways?
Manufacturable? What about a case for moderate toxic payloads? What
about the sensitivity of cytotoxic agents to multidrug resistance
Progress in site-specific conjugation modalities, optimization of linkers
with balanced stability and identification of novel, potent cytotoxic
agents are expected to pave the way for a better understanding of factors
such as ADC efficacy, PK and safety. What are the
complexities? A robust clinical pipeline, evolving clinical data,
technological advancements and a better understanding of the biology of
cancer and hematological malignancies, may help in the development of
novel ADCs. What are the challenges? What are your expectations?
5:45 Networking Reception in the Exhibit Hall with Poster Viewing
7:00 End of Day
THURSDAY, APRIL 28
8:00 am Morning Coffee
8:30 Chairperson’s Remarks
Greg Adams, Ph.D., Chief Development Officer, Viventia Biotech
8:35 Engineering a Tumor-Specific, Next-Generation Anti-EGFR ADC Development Candidate
Christopher D. Thanos, Ph.D., Senior Director, Biotherapeutics Discovery, Halozyme Therapeutics, Inc.
9:05 Selected Poster Presentation I:
Site-Specific Antibody Drug Conjugates Using a Unique Lysine Residue
Alex Nanna, Graduate Student, Cancer Biology, Scripps Research Institute
Current strategies to produce site-specific ADCs mostly rely on mutations or non-selective conjugation chemistry. Here we present a novel strategy to produce site-specific ADCs using a chemically programmable antibody. This approach is mutation-free and
drug conjugation proceeds rapidly at neutral pH in only 2 hours. Extensive optimization was required combining synthetic chemistry and antibody engineering to product potent ADCs targeting human epidermal growth factor receptor 2 (HER2), folate receptor
1 (FOLR1) and CD138.
9:20 Selected Poster Presentation II:
Antibody-Drug Conjugates Targeting Sialyl-Tn (STn) Demonstrate in vitro and in vivo Anti-Tumor Efficacy
Jillian Prendergast, Ph.D., Scientist I, R&D, Siamab Therapeutics
Targeted therapeutics today must differentiate between normal and malignant tumor cells. At Siamab Therapeutics, we have focused on a target - Sialyl-Tn (STn) - that shows marked differences in expression between normal and cancer tissues; its presence
in tumors is also associated with poor prognosis and reduced survival. Clinical approaches to targeting STn have thus far consisted of an STn vaccine (Theratope), which failed in advanced clinical trials due to poor efficacy, but demonstrated strong
safety with STn as a target. Early generation commercial mouse antibodies have targeted STn, but have poor specificity, binding additional glycans or proteins. Siamab Therapeutics has addressed these concerns by developing a highly specific, high
affinity anti-STn mAb panel. Lead candidates demonstrate single digit nanomolar EC50s in ELISA/flow cytometry assays, target selective cell internalization, and STn specific glycan binding on Siamab's proprietary glycan array. Tumor microarray experiments
revealed a desirable staining pattern and frequency across several cancer indications with minimal to no staining of normal tissues. We have formatted these lead anti-STn mAbs as antibody drug conjugates (ADCs) and they demonstrate target specific
cell killing in vitro with single digit IC50s. A multiple dose ICR SCID subcutaneous xenograft in vivo cancer model demonstrated statistically significant tumor growth inhibition (%T/C) ranging from 3.0 - 3.6% of these anti-STn ADCs compared to vehicle
alone. Humanization was recently completed for these lead mAbs, and target specificity, affinity and cytotoxicity were maintained with additional validation underway. Our data demonstrates that high-affinity, STn-specific mAbs show promise as therapeutics
for solid tumors.
9:35 Delivering the Future of Oncology
– Manufacturing Next Generation Bioconjugates & Combination Therapies
Thomas Rohrer, Senior Manager, Antibody Drug Conjugation Project Evaluation, Lonza
- A brief history of oncology treatments and bioconjugates
- Lessons learned and challenges associated with ADCs
- What does the future look like for ADCs? Novel conjugation technologies, cytotoxic drugs, and different linker chemistries
- How the experiences from one manufacturing technology may be applied to the future of oncology
10:05 Coffee Break in the Exhibit Hall with Poster Viewing
11:05 A Plug-and-Play Approach to Antibody-Based Therapeutics via a Chemoselective “Dual Click” Strategy
Vijay Chudasama, Ph.D., MSc, Lecturer, Chemistry, University College London
There is a clear demand for the construction of novel antibody-drug conjugate (ADC) platforms that offer greater stability, homogeneity and flexibility. A significant step towards the ideal platform for next generation antibody-based therapeutics is presented.
Our technology provides decorated antibody constructs that are highly stable, with complete retention of antibody binding/structure post-modification. It combines site-specific functionalisation with exceptional versatility via the functional re-bridging
of interchain disulfide bonds native to antibodies.
11:35 Improving the Therapeutic Window of an Antibody-Drug Conjugate by a New Stable Conjugation Method
Jinwon Jung, Ph.D., Principal Scientist, R&D Center, ABL BIO
To overcome the limitation of ADC due to off-target toxicity and narrow therapeutic window, we have developed s new conjugation technique that attaches drugs to N-terminal of an antibody through amine bond by reductive alkylation reaction (NTERM). NTERM
ADC showed superior in vitro and in vivo stability as well as tolerability than commonly used thiol-conjugate and lysine conjugate. Therefore, NTERM can be a novel conjugation method to improve therapeutic window.
12:05 pm A Non-Genetic Approach to ADCs with Improved Therapeutic Index with GlycoConnect™ and HydraSpace™ Technology
Floris van Delft, Ph.D., Co-Founder and CSO, Synaffix
GlycoConnect™ is a highly efficient technology to obtain, without protein engineering, antibody-drug conjugates (ADCs) in a two-stage process involving (a) enzymatic N-glycan remodeling and (b) copper-free click attachment of payload. Conjugation
of highly hydrophobic payloads is accommodated with polar HydraSpace™ technology. Excellent in vivo efficacy and high tolerability is demonstrated, thus paving the way for the next generation of ADCs with an improved therapeutic index.
12:35 End of Antibody-Drug Conjugates I: New Ligands, Payloads and Alternative Formats
5:15 Registration for Dinner Short Courses