Cambridge Healthtech Instituteの第13回年次
Driving Clinical Success in Antibody-Drug Conjugates
- 5:00 pm Main Conference Registration1:00 pm
Recommended Pre-Conference Short Course2:00 pm
SC4: An Introduction to Protein Degraders: A Focus on PROTACs
*Separate registration required. See short courses page for details.
Recommended Dinner Short Course6:30 pm
SC8: CAR T Cells: Improving Safety While Retaining Therapeutic Activity
*Separate registration required. See short courses page for details.
Registration and Morning Coffee7:30 am
Trastuzumab Deruxtecan - Successful ADC Development from Payload Selection to Multi-Indication Approval
ENHERTU (T-DXd; ENHERTU) is a HER2-directed ADC, using Daiichi Sankyo’s proprietary DXd ADC technology, consisting of a HER2 monoclonal antibody attached to a potent topoisomerase I inhibitor payload, an exatecan derivative. Remarkable features include a stable cleavable linker and a bystander effect in tumor tissue. T-DXd has demonstrated superior efficacy compared to standard-of-care therapies in different tumor types such as breast and gastric cancer and lines of therapy. This presentation will provide an overview of the development of T-DXd including recent data.
Mirvetuximab Soravtansine: A Novel FR Alpha-Targeted ADC for Platinum-Resistant Ovarian Cancer
Mirvetuximab soravtansine (MIRV) is a novel antibody-drug conjugate targeting folate receptor alpha. This talk will review clinical safety and efficacy data of MIRV monotherapy in platinum-resistant ovarian cancer from the pivotal SORAYA and MIRASOL trials that led to submission to the FDA. Efficacy and safety data of MIRV with bevacizumab from the FORWARD II trial will be reviewed, leading to a discussion of next steps in clinical development for MIRV.
New data will be presented highlighting the improved efficacy and tolerability of SMARTag® ADCs as compared to marketed ADCs against the same targets. Key features include:
• Site-specific conjugation with optimized payload placement on the antibody
• Proprietary tandem-cleavage cleavable linkers that are stable in the circulation
• Proprietary topoisomerase I inhibitor technology with DAR 4 and DAR 8 options
• Outstanding pharmacokinetics, which drive the improved efficacy and tolerability
Coffee Break in the Exhibit Hall with Poster Viewing10:00 am
The Current Landscape of DNA Damaging ADC Payloads: Which Mechanism of Action Works the Best?
Many ADCs contain DNA-interactive payloads with different mechanisms of action including DNA cleavage, G/G-crosslinking, mono-G-alkylating, mono-A-alkylating and topoisomerase inhibition. A number of ADCs with DNA-cleaving and topoisomerase inhibiting payloads have been approved, and two with mono-G-alkylating and mono-A-alkylating payloads are in late-stage clinical trials. This presentation will discuss the advantages and disadvantages of the various mechanisms, with a focus on efficacy and side effects.
Improved Therapeutic Index with Novel Tumor-Selective Linker Technologies
While ADCs are designed to improve the therapeutic index (TI) compared to traditional chemotherapeutic agents, on- and off-target toxicities remain a challenge in developing ADCs as effective cancer therapies. One emerging approach to improve the TI of ADCs is to incorporate tumor-selective chemistries for the release and/or activation of the ADC payload. These innovative designs have been shown to improve both the MTD and toxicity profile in preclinical models, and recently, in the clinic.
Antibody Targeted Amanitin Conjugates: A New Payload Provides New Options for Cancer Therapy
ATACs comprise a new class of antibody-drug conjugates (ADCs) using amanitin as toxic payload. Amanitin binds to the eukaryotic RNA polymerase II and thereby efficiently inhibits the cellular transcription process. Non-dividing as well as antigen low expressing cells can also be targeted. First ATACs entered Phase I/IIa clinical trials in 2022. HDP-101 is directed against BCMA for the treatment of relapsed and refractory Multiple Myeloma patients.
- ATAC introduces a new payload with a new mode of action into oncology therapy
- Two ATACs are in Phase I
- HDP’s lead program HDP-101 is targeting BCMA for r/r Multiple Myeloma
Luncheon in the Exhibit Hall and Last Chance for Poster Viewing12:10 pm
Tumor-Targeted Activation of the STING Pathway with Immunosynthen ADCs
Activating an innate anti-tumor immune response could be an effective therapeutic strategy in oncology, and an ADC could enable this approach by localizing activation to the tumor microenvironment. Tumor-targeted Immunosynthen ADCs activate STING in tumor-resident immune cells and in tumor cells (“the 1-2 punch”). XMT-2056 is a HER2-targeted Immunosynthen ADC that binds a novel HER2 epitope and has entered clinical development. The mechanistic translational studies presented could guide clinical development.
TPD2 Conjugates - Antibody-Enabled Dual Precision Targeted Protein Degraders
TPD2, dual precision targeted protein degradation merges the power of targeted protein degraders with the precision of antibodies to deliver molecular glues or bifunctional degraders intracellularly with cell-specificity, overcomes many of the challenges of small molecule degraders, and increases the therapeutic index of degraders. Using the TPD2 approach, highly specific GSPT1 degrader platform was developed that shows promising efficacy against various hematological malignancies and solid tumors. Two TPD2 GSPT1 degraders in clinical/late preclinical testing, ORM-5029 for breast cancer and ORM-6151 for AML will be discussed. Furthermore, a second TPD2 platform PROTAb used to deliver bifunctional degraders will also be highlighted.
Monoclonal antibodies treatment modalities and are expected to generate up to $80bn world wide sales over the next 5 years. Competition from biosimilars is fierce and drug developers are looking to extend their antibody therapies by coupling protein drugs with active payload components. This talk describes how we can leverage the success of antibody drugs to generate novel therapies to provide new options for previously untreated disease.
Networking Refreshment Break2:50 pm
Targeting STING to CCR2+ Cells via an Immune Stimulating Antibody Conjugate
Myeloid cells are present in most human solid tumors and they exert local immunomodulatory functions. STING signaling in intratumor myeloid cells can enhance interferon (IFN) production, boost local adaptive anti-tumor immunity, and could synergize with other anti-cancer therapies. We discuss nonclinical data for a novel iADC, TAK-500, which selectively activates STING in CCR2-expressing cells to enable systemic delivery, favor intratumor accumulation of the active compound, and achieve anti-tumor immunity.
Developing an Immunostimulatory Antibody Drug Conjugate with Optimized Linker and Payload Components
TLR 7/8 agonists stimulate innate immune effector cells and prime downstream T cell activation to drive potent and lasting anti-tumor immunity. However, direct administration of TLR 7/8 agonists in cancer therapy has been limited by systemic toxicities. Antibody-drug conjugates are a clinically validated drug platform providing drug delivery to targeted cells to improve tolerability and efficacy. We have developed a TLR7/8 agonist that was optimized for its physical and biological properties as an ADC payload. Combining this payload with an optimized drug linker design, our ADC demonstrated potent and durable anti-tumor activity in several syngeneic tumor models.
Close of Day4:20 pm
Registration Open7:00 am
Interactive Discussions are informal, moderated discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each discussion will be led by a facilitator who keeps the discussion on track and the group engaged. To get the most out of this format, please come prepared to share examples from your work, be a part of a collective, problem-solving session, and participate in active idea sharing. Please visit the Interactive Discussions page on the conference website for a complete listing of topics and descriptions.
TABLE 3: ADCs in the Era of Immunotherapy - Their Current Roles and Potential Future - IN-PERSON ONLY
- Antibody-drug conjugates (ADCs) have achieved 8 new approvals in the past 5 years.
- ADCs can initiate immunogenic cell death without the broad immunosuppression of small molecule chemotherapy and interact via their Fc-domain.
- Discussion on current therapeutics that are being combined with checkpoint inhibitors, anti-VEGF therapy, and other treatments to potentially increase the immune response.
- Conversation about new avenues that are being developed to maximum the immune response with these novel therapeutics.
TABLE 4: Next-Generation Antibody Drug Conjugates: What Do We Need to Do for the Next Major Step Up? - IN-PERSON ONLY
ELU001 - A Targeted C'Dot Drug Conjugate (CDCs) for the Treatment of Folate Receptor Alpha Expressing Tumors
ELU001 is an anti-FRa CDC targeted by 13 folic acid moieties and delivering 21 exatecan payloads. Preclinically ELU001 penetrates into and is retained by tumors including brain tumors and efficiently targets and kills tumor cells in vitro and in vivo that express low, moderate, and high levels of FRa. Non-clinical toxicity studies of ELU001 revealed a lack of the common ADC-related toxicities. ELU001 is currently being evaluated in clinical trials.
Exploiting Novel Protein Domain Architectures to Deliver Next-Generation Mono- and Bispecific Protein-Drug Conjugates Targeting ROR1
A novel PDC platform has been developed, which exploits the properties of small protein domain binders to deliver homogenous conjugates in monospecific, biparatopic, and bispecific formats. This approach has delivered development candidate ADP-c389, a novel, selective VNAR-based PDC targeting ROR1, that provides a differentiated approach for the treatment of ROR1-positive solid tumours. Capitalising on the co-expression pattern of ROR1 and EGFR, a series of bispecific PDCs have been developed, which are highly promising next-generation agents for the treatment of additional solid tumour indications.
The Influence of DM1, MMAE, and MMAF on Biodistribution and Preclinical Therapeutic Efficacy of Affibody-Based Drug Conjugates
Affibody molecules are small engineered alternative scaffold affinity proteins that can be site-specifically loaded with cytotoxic drugs to create homogenous conjugates with a desired drug-to-carrier ratio. The presentation will explore targeting of EGFR, HER2, and HER3 with affibody-based drug conjugates. It will also describe the impact on biodistribution and in vivo cytotoxic efficacy of HER2-targeting drug conjugates loaded with auristatin and maytansine-derived payloads.
Networking Coffee Break10:30 am
NOVEL ADC ENGINEERING & CONJUGATION
Dual Precision Conjugates Reduce Resistance and Promote Anti-Tumor Immunity
Emerging clinical data show that precisely conjugated homogeneous ADCs more efficiently target tumors with potential benefit to patients with lower target antigen levels. Now, dual conjugation chemistries promise further advances in targeted therapies exemplified by Immunomodulatory ADCs (iADCs) that cause tumor cell disruption together with innate immune cell stimulation and result in anti-tumor immunity, and ADC2 ‘s dual-conjugated payloads that disrupt DNA while simultaneously impairing resistance to drive synthetic lethality.
Dual-Function Antibody Conjugates: Combining Multiple Modes of Action to Maximize ADC Efficacy
We will describe the design, optimization, and preparation of dual-mode ADCs which combine an immuno-stimulant payload with a cytotoxic payload. The results of early proof-of-concept studies will be shown to demonstrate that the resulting dual-payload ADCs retain properties affiliated with both classes of payloads. Challenges associated with biophysical properties will also be addressed.
Bispecific Antibody Drug Conjugates for the Treatment of Acute Myeloid Leukemia - A Safer & More Efficacious Option for Patients?
The development of antibody drug conjugates (ADCs) for the treatment of acute myeloid leukemia (AML) has been limited by the availability of unique disease-specific antigens. Gemtuzumab ozogamicin (GO) is the only ADC approved for use in CD33+ AML patients, but is associated with dose-limiting toxicities. The use of bispecific antibodies represents a novel approach to the development of ADCs with the potential of a more efficacious and safer treatment option for patients in the future. Here, we describe the twin antigen validation and target cell selectivity of an aCD7/aCD33 bispecific ADC.
Close of Summit12:30 pm