Radiopharmaceuticals are creating more interest than ever. To live up to their blockbuster promise, RPs have to be clearly better than competing conventional therapies, particularly ADCs. A framework to systemically assess how RPs can compete will be introduced. RPs will compete in early lines of therapy implying that they will be used in combination-requiring thinking differently about clinical development. Imaging tracers can support development but add complexity, and change the economics compared to a therapeutic alone. Finally the choice of radioisotopes defines product characteristics but can also drive complexity and cost.

This presentation explores the synergy between precision therapies and diagnostics, and discusses how advanced diagnostics enable patient selection for innovative treatments. The talk will highlight the convergence of in vivo and in vitro techniques, particularly in the emerging area of Radioligand Therapies (RLT) where we see need for incorporating “liquid biopsy” approaches to complement imaging. We will examine case studies showcasing successful applications of this approach and consider future directions.

Radiopharmaceutical therapy (RPT) enhances tumor response to immune checkpoint inhibitors (ICI) in preclinical models. Here, we present results of preclinical investigation of the effects of treatment sequence, radioisotope properties, and tumor immunogenicity on the therapeutic interactions between RPT and ICIs in syngeneic murine tumor models.

The development of immune checkpoint blockades has revolutionized treatment paradigms for metastatic cancer. However, despite gains in tumor response and survival many patients eventually develop resistance to immunotherapy treatments. One strategy to enhance efficacy of immunotherapy is through the use of targeted radionuclide therapy which can deliver immunomodulatory radiation to metastatic sites. We will highlight current results and future directions on the development of combination immunotherapy and radionuclide therapy treatments.

Scalability issues have impeded several radiopharmaceutical launches in both diagnostic and therapeutic applications. Historical challenges with scalability have resulted in a lack of investment in certain isotopes and disruptions in patient care for others. To mitigate these issues in the future, it is crucial to select supply chains that inherently provide scalability. How can we ensure scalability in future radiopharmaceutical supply chains to avoid past pitfalls?

When designing production and quality control processes during clinical supply, it's important to consider how these processes will be communicated to regulators and inspectors as the drug moves into the approval process. Early planning for validation and verification studies and documentation of the decisions made can be instrumental in educating these parties and can help make the approval process move smoothly.

We have developed an advanced peptide discovery platform that identifies peptide candidates for peptide radionuclide conjugates (RDCs). This platform combines Peptide Information Compression Technology (PICT), Disulfide-Rich Peptides (DRPs) phage display, animal toxin, nano macrocyclic, and virtual peptide libraries. It rapidly identifies potent peptide hits with antibody-like affinity (sub-nM to pM), enhanced serum stability (hours to days), and bi-functional capabilities, optimized to bind multiple receptor targets within 6 months.

• Time constraints from production, QC to delivery
• Pros and cons of decentralized production
• The need for specialized production facilities and highly-skilled personnel 
•  Regulatory compliance 
•  Supply chain logistics 
•  Waste management

We utilize 1,4,7,10-tetraazacyclododecane-N, N’, N’’, N’’’-tetraacetic acid (DOTA) radiohapten capture to obtain high therapeutic indices during pre-targeted radioimmunotherapy (PRIT). This strategy, known as ‘DOTA-PRIT,’ involves using anti-tumor antigen/anti-(DOTA) radiohapten bispecific antibodies (BsAb) and DOTA-radiohaptens for therapy with lutetium-177 (177Lu) and actinium-225 (225Ac). Recently, we introduced the SADA (Self-Assembling Dis-Assembling) BsAb platform, and a Phase 1 trial of GD2-SADA + [177Lu]Lu-DOTA in GD2-expressing solid tumors is underway (NCT05130255).

We present the latest findings from preclinical studies on self-assembling and disassembling (SADA) bispecific fusion proteins directed against solid and hematological tumors that overexpress the GD2 glycolipid (GD2-SADA) and CD38 glycoprotein (CD38-SADA), respectively. Our studies support a two-step approach to pretargeted radioimmunotherapy, clinical development of which is now underway with GD2-SADA and Lutetium-177 (Lu-177)-DOTA (NCT05130255) and CD38-SADA and Lu-177-DOTA (NCT05994157).

Radioimmunotherapy targets cancer cells using antibodies but is limited by radiation exposure to healthy tissues. The modular theranostic PreTarg-it system uses tumor-penetrating bispecific antibodies and radionuclide-labeled chelators fused to the HSG hapten. Pilot studies with the bispecific antibody ON105 targeting oxMIF and the 177Lu-labeled DOTA-di-HSG hapten (IMP288) showed significant tumor regression in colorectal and pancreatic cancer mouse models, indicating potential for treating challenging solid tumors and late-stage malignancies.

Breast cancer is a major cause of cancer-related death among women; molecular radiotherapy may improve the outcomes. HER2 is an important oncogenic driver in a large subset of breast cancers. Affibody-based HER2-specific clinical imaging has demonstrated pharmacological access to the target in women with metastatic disease. Incorporating the same targeting vector with a biodistribution-modulating albumin binder, ABY-271, is in advanced preclinical development for targeted radioligand therapy.

Single-domain antibodies (nanobodies), selected by means of synthetic libraries, have a number of advantages for development into radiopharmaceuticals. Due to their small size, they penetrate deeper into target tissue, they have a simpler structure, and they are much more stable, easier to functionalize, faster, and cheaper to make. Here, Cortalix presents the selection of single-domain antibodies for novel radiopharmaceutical targets for fibrosis and fibrotic cancers, such as colon cancer.

DEP dendrimer nanparticles are a versatile, clinically validated platform that enables targeted and precision delivery and customized biodistribution profiles for cancer radiotheranostics. DEP dendrimers can be tailored in size to address shortcomings of small molecule and large antibody targeting, and can carry different payloads and different targeting moieties. The biodistribution and efficacy of targeted DEP dendrimer radiotheranostics show a favorable biodistribution profile, with rapid blood clearance and significant tumor accumulation, coupled with anticancer activity in models of human disease.

Glypican-3 (GPC3) is a membrane-associated proteoglycan that is significantly upregulated in hepatocellular carcinoma (HCC)-the most common type of liver cancer-and in neuroendocrine prostate cancer (NEPC), a rare but lethal subtype for which there are few treatments. Because HCC- and NEPC-selective imaging is critical for diagnosis, monitoring treatment response, and surveillance-and novel therapies are needed to improve outcomes-GPC3 represents a promising radiotheranostics target.

When patients with hepatocellular carcinoma (HCC)-the most common type of liver cancer-are treated with embolization or radiotherapy, often clinicians cannot distinguish non-viable from viable/residual/recurrent disease with conventional CT/MRI imaging. While positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose is used for other cancers, it is taken up in just 50% of HCC. CD24 is overexpressed in HCC and represents a promising radiopharmaceutical target for the imaging and treatment of HCC.