- 抗体药物复合体的临床开发进展 -
Today, there are about 80 ADCs in clinical development, with 2 to 3 novel ADCs likely to be approved within the next few years. The clear clinical benefit of ADCs is only overshadowed by its dose-limiting toxicities, but recent improvements in technology combined with clinical data from past ADC programs and related fields are helping to shape the next generation of bioconjugates. At CHI's Clinical Progress of Antibody-Drug Conjugates conference, we invite scientists to share their clinical updates and and lessons learned that can help inform next-generation ADC design and development.
Day 1 | Day 2
12:00 pm Registration
12:35 Luncheon in the Exhibit Hall with Poster Viewing
PRECLINICAL OUTCOMES AND CLINICAL TRANSLATION
1:40 Chairperson’s Opening Remarks
Rakesh Dixit, DAPT, PhD, President & CEO, Bionavigen
1:50 KEYNOTE PRESENTATION: Key Learnings from Successful and Failed ADCs
Rakesh Dixit, DAPT, PhD, President & CEO, Bionavigen
With five approved ADCs and one recombinant immunotoxin combined with the great potential of approval of at least 4 additional ADCs in the next 2 years, there is renewed enthusiasm and momentum in the world of oncolytic ADCs. However, the success in oncolytic ADCs has come with high failures. The presentation will provide a comprehensive review as follows:
- What is common among clinically successful ADCs?
- What went wrong with some clinically unsuccessful ADCs?
- Top five lessons learned from the development of ADCs in the last two decades
- Innovations in creating designer ADCs with fit-for-purpose
2:20 Application of PK/PD M&S for Preclinical-to-Clinical Translation of ADCs
Dhaval Shah, PhD, Associate Professor, Pharmaceutical Sciences, University of Buffalo
This talk will highlight how preclinical experiments can be used in conjunction with PK/PD modeling and simulation to support the discovery, development and preclinical-to-clinical translation of novel ADCs. The talk will also focus on novel P/PD-based strategies to improve the therapeutic index of ADCs.
2:50 DAC-002: A Potent Antibody-Drug Conjugate Targeting TROP2-Positive Solid Tumors
Xiaomai Zhou, PhD, Vice President, Biology, Hangzhou DAC Biotech, China
A novel hydrophilic Tubulysin B derivative payload was conjugated to an anti-Trop2 antibody via a non-cleavable linker with an incorporated slow releasing mechanism. Preclinical studies have demonstrated potent anti-tumor activity of this ADC in Trop2-positive triple negative breast cancer, lung cancer and gastric cancer xenograft models. Furthermore, this ADC was well tolerated in cynomolgus monkeys and rats in acute and chronic toxicology studies. Based on the promising data, an IND has been filed at Chinese FDA and the filing at US FDA is underway.
3:20 Sponsored Presentation (Opportunity Available)
3:50 Networking Refreshment Break
4:20 Motivating Clinical Development of TAK-164 with Preclinical Studies
Adnan Abu-Yousif, PhD, Associate Director, IO Biology, Takeda Pharmaceuticals
TAK-164 is a second-generation investigational ADC, comprised of a human anti-GCC monoclonal antibody conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. Here, we discuss ongoing preclinical studies that inform the potential of TAK-164 in GCC positive tumors.
4:50 LCB14 - A Next Generation anti-HER2 ADC with Industry-leading DAR precision, plasma stability and tumor-selective linker activation: Progress toward the clinic
Jeiwook Chae, PhD, Chief Business Development Officer, LegoChem Biosciences
LCB14 is an antibody-drug conjugate (ADC) composed of trastuzumab conjugated to Monomethyl auristatin F (MMAF) at a drug-to-antibody ratio (DAR) of 2. Here, we discuss preclinical studies that inform the potential of LCB14 for the next best-in-class HER2 targeting ADC with the industry-leading therapeutic window by virtue of LCB’s site-specific conjugation and a novel linker chemistry that improves stability of ADCs in blood circulation, effectively prevents premature drug release, and efficiently facilitates the liberation of the drug at the targeted tumor cells. In addition, this presentation highlights LCB’s tumor-selective and ultra-potent DNA-crosslinking payload with superior efficacy and reduced toxicity with case studies of ongoing best-in-class ADCs at preclinical stage.
5:20 End of Day
5:15 Registration for Dinner Short Courses
5:45-8:15 pm Recommended Dinner Short Course*
SC13: Design Strategies & Development of ADCs
*Separate registration required.
Day 1 | Day 2
8:00 am Registration and Morning Coffee
PROGRESS IN THE CLINIC
8:30 Chairperson’s Remarks
John Lambert, PhD, Independent Consultant
8:35 Belantamab Mafodotin – Driving Innovation for Next Generation Therapy in Multiple Myeloma
Axel Hoos, MD, PhD, Senior Vice President, Oncology R&D, GSK
BCMA has become the leading new target for multiple myeloma with several BCMA-targeting agents in clinical development. GSK’s belantamab mafodotin is an antibody-drug conjugate which has recently completed a pivotal study in 4th line of treatment in patients with multiple myeloma. This presentation provides an update on the pivotal data and overall clinical program of belantamab mafodotin.
9:05 AVID100: Phase 2 Tumor Selective Anti-EGFR ADC with Novel Mechanism of Action
Maureen O’Connor-McCourt, PhD, CSO, Forbius
AVID100 is the most advanced and broadly active anti-EGFR ADC in clinical development, targeting both wild-type and mutant forms of EGFR. AVID100 is highly potent and selectively cytotoxic against EGFR-expressing cancer cells, while sparing normal EGFR-positive keratinocytes. Phase 2a clinical trials are ongoing in patients with EGFR-overexpressing SCCHN, sqNSCLC and TNBC.
9:35 TRPH-222: A Next Generation ADC Targeting CD22
Nancy Levin, PhD, Vice President, Development, Triphase Accelerator
TRPH-222 is a CD22-directed ADC, constructed via a novel, site-specific (SMARTag™) conjugation approach, resulting in highly controlled and reproducible drug loading. TRPH-222 is being studied in relapsed and/or refractory B-cell lymphoma patients in a phase 1 clinical trial (NCT03682796); currently the trial is enrolling patients in the dose-escalation phase, with promising tolerability, PK, and PD, as well as early signs of clinical efficacy in this single agent study.
10:05 Networking Coffee Break
10:35 Combining ADCs and Immunotherapy: Mechanistic Insights and Clinical Observations
Bob Lechleider, MD, Senior Vice President, Development, Seattle Genetics
MMAE-based ADCs have demonstrated the potential to change the natural history of multiple cancers. MMAE, the cytotoxic payload, has been shown to induce immunogenic cell death. Combining MMAE-based ADCs with immunotherapy has the promise of augmenting the benefit of each of these therapies.
11:05 ZW49: Combining Zymeworks’ Platforms to Expand the Therapeutic Window of ADCs in HER2-Positive Cancer
Rupert Davies, PhD, Director, Translational Sciences, Zymeworks
HER2-targeted therapies have transformed the treatment of patients, but there remains a need for well-tolerated and effective treatments across a range of HER2 expression levels. ZW49 is a bispecific antibody-drug conjugate that combines the ZymeLink™ linker-payload with the unique mechanisms of action of a biparatopic anti-HER2 Azymetric antibody. ZW49 has the potential to address the unmet medical need across a range of HER2 expressing cancers.
11:35 Antibody-Drug Conjugates: Are We There Yet?
Anthony Tolcher, PMP, FRCPC, FACP, Director, Clinical Research, CEO & Founder, Next Oncology
12:05 pm Antibody-Drug Conjugates as Targeted Conditioning Agents for Bone Marrow Transplant: Progress toward the Clinic
Charlotte McDonagh, PhD, Vice President, Biotherapeutics, Magenta Therapeutics
Patient outcomes can be greatly improved by a bone marrow transplant in multiple disease settings, including autoimmune diseases and hematologic disorders. Prior to transplant, patients are conditioned by removing their own bone marrow stem cells using poorly tolerated toxic, non-selective chemotherapy and radiation. This presentation will highlight preclinical proof of concept data demonstrating that antibody-drug conjugates may be safer, targeted agents for patient preparation with the aim of extending the use of curative bone marrow transplant and improving outcomes for patients.
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:05 Networking Refreshment Break
LESSONS LEARNED FROM PAST ADC PROGRAMS AND RELATED FIELDS
1:35 Chairperson’s Remarks
Greg Thurber, PhD, Associate Professor, Chemical Engineering and Biomedical Engineering, University of Michigan
1:40 A New Mechanism of Malignant Cell Resistance to Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
Louis Weiner, MD, Director, Oncology, Lombardi Comprehensive Cancer Center, Georgetown University
ADCC provides a model for uncovering immune resistance mechanisms. We have continuously exposed different cancer cell lines to KIR-deficient NK92-CD16V effector cells and ADCC-promoting monoclonal antibodies. We show that the induction of ADCC resistance involves genetic and epigenetic changes that lead to a general loss of target cell adhesion properties required for the establishment of an immune synapse, killer cell activation, and target cell cytotoxicity. These findings have implications for resistance to diverse forms of cancer immunotherapy.
2:10 Microdistribution of Antibody Distribution in Clinical Trials Using Fluorescently Labeled Anti-EGFR Antibody in Multiple Tumor Types
Eben Rosenthal, MD, Cancer Center Medical Director, Otolaryngology, Stanford University
Systemically-administered labeled antibodies in cancer patients prior to surgery has allowed us to successfully measure antibody concentration in normal and tumor tissues. The biggest impact of this strategy is the ability to localize the antibody within tissues at the cellular level. We hypothesize that near-infrared fluorescently labeled antibodies can be leveraged to estimate the dose at which the antibody reaches maximal tumor saturation, most notably for antibody-drug conjugates.
2:40 Radiohapten Capture Radioimmunotherapy for Cures of Human Tumor Xenografts in Mice
Steven Larson, MD, Head, Larson Lab, Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Over the past several years, we have developed an antibody-based platform approach for parenterally-targeted radiotherapy with a goal of cures without histologic evidence of radiotoxicity in laboratory models of highly radioresistant solid tumors. Using a radiohapten capture system developed in collaboration with the Wittrup Laboratory of MIT, we have demonstrated proof of principle with beta and alpha emitting radionuclides in 3 solid tumors (antigen targets): neuroblastoma (GD2), breast cancer (Her 2) and colon cancer (A33).
3:10 Modeling Target-Mediated Drug Disposition to Design More Effective Therapeutics
Donald Mager, PharmD, PhD, FCP, Professor & Vice Chair, Pharmaceutical Sciences, University of Buffalo
3:40 End of Conference