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.

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.

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
• Phase I study using ATAC is ongoing
• HDP’s lead program HDP-101 is targeting BCMA for r/r Multiple Myeloma
  

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, 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.

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.

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.

• 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.

• Radical or incremental innovations - novel formats, conditional activation, unconventional targets or payloads
• Which innovation will make a real impact in the treatment of solid 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.

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.

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.

Multivalent proteins including bispecifics, biparatopic agents, and antibodies provide powerful tools to engineer binding and delivery under specified conditions. However, the complexity of these agents, challenges in (high-throughput) expression, and often sophisticated assays to assess efficacy are hurdles to their development. Here, we use a series of humanized single-domain antibodies (Humabodies) to outline the impact of design features including valency, affinity, and structure to provide guiding principles for development.

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.

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.

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.