Antibody-Drug Conjugates

antibody-drug conjugates

The experimental designs for antibody-drug conjugates (ADCs) goes back to more than 50 years, yet the success associated with ADCs have gained considerable triumph in recent years. Belonging to the class of highly complex engineered therapeutics, ADCs comprise of monoclonal antibodies specific to the surface target antigens linked via a chemical linker; their design makes them the most efficient targeting agents for a tumor cell.

In 2000, Gemtuzumab ozogamicin (Pfizer) gained the very first approval worldwide for patients with relapsed acute myelogenous leukemia. Throughout the years, there has been a tremendous advancement with several other ADCs approvals, such as Brentuximab vedotin by Seattle Genetics, Ado-trastuzumab emtansine by Roche, Inotuzumab ozogamicin by Pfizer, Polatuzumab vedotin by Roche, Enfortumab Vedotin-ejfv by Astellas, and Belantamab mafodotin by GSK. They all are designed to target multiple indications such as Hodgkin Lymphoma (HL) and ALCL, cutaneous T-cell lymphoma (CTCL), HER2-positive early breast cancer (EBC), CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL), diffuse large B -cell lymphoma (DLBCL), locally advanced or metastatic urothelial cancer, relapsed or refractory multiple myeloma, and others.

The use of MAB directed delivery can confer a therapeutic index to highly potent cytotoxic drugs, increasing both the efficacy and safety of the therapy. It also minimizes normal tissue exposure that results in an improved therapeutic index and less damage to the surrounding healthy tissue. The clinical efficacy of the ADCs particularly depends on the accurate selection of four parameters, including tumor targeting, antibody, cytotoxic payload, and method of antibody linkage to the payload.

With around 7–8 ADCs already approved in the market, a great deal of effort has also been made by the pharmaceutical companies to overcome the technological barriers associated with ADCs, thereby leading to ~100 ADCs that are currently undergoing preclinical and clinical trials.

As various ADCs have been approved, with numerous additional agents in development (targeting an expanding range of tumor antigens, including HER2, HER3, Trop-2, as well as several other antigens), ESMO2020 is a crucial platform to watch out for its recent progress.

Daichii Sankyo is all set up to present its new research data for patritumab deruxtecan (U3-1402), a HER3 directed ADC, in patients with EGFR-mutated (EGFRm) NSCLC and ENHERTU (fam-trastuzumab deruxtecan-nxki), HER2 low and advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma at the conference. Its ADC portfolio currently consists of seven ADC’s in the development, among which five includes ENHERTU and DS-1062 (TROP2 directed ADC), being jointly developed and commercialized globally with AstraZeneca; while patritumab deruxtecan, DS-7300 (B7-H3 directed ADC), and DS-6157 (GPR20 directed ADC), under development through a strategic research collaboration with Sarah Cannon Cancer Institute. Every ADC is engineered using Daiichi Sankyo’s proprietary and portable DXd ADC technology to target and deliver chemotherapy inside cancer cells that express a specific cell surface antigen.

Furthermore, Gilead is all set up to acquire Immunomedics, which will provide Gilead with Trodelvy (sacituzumab govitecan-hziy), a first-in-class Trop-2 directed ADC, for which Gilead is trying to expand the current use for earlier lines of therapy in TNBC. The drug recently got accelerated approval in April by US FDA for 3L+ triple-negative breast cancer, which has shown significant efficacy benefit as compared to chemotherapy by driving early adoption, and its focus is to become the SOC in advanced TNBC. The company is planning to present five presentations during ESMO2020, including full results of Phase III ASCENT (3L+ mTNBC) and much awaited updated results of Phase II TROPHY U-01 studies (3L mUrothelial cancer), with other ongoing registrational studies in HR+/HER2- mBC and multiple solid tumor types.

ESMO this year is also featuring data on Trodelvy combinations, with ADC being under development alongside Clovis’s Rubraca and Roche’s Tecentriq.

Additionally, GlaxoSmithKline is ready to present new data in ESMO, including the recent European and FDA approval for BLENREP (belantamab mafodotin) for patients with relapsed/refractory multiple myeloma.

And as far as novel mechanisms go, Mersana’s NaPi2b antibody-drug conjugate XMT-1536 will also attract attention during ESMO2020. Genmab, on the other hand, is going to present its late-breaking oral presentation for the results from Phase II innovaTV 204 study evaluating tisotumab vedotin in patients with recurrent or metastatic cervical cancer.

Overall, DelveInsight believes that ADCs are going to be a key focus area during ESMO2020. Considering the transformative model for ADC, the pace of development of ADCs has accelerated considerably over the past few years. Growth in the number of registered ADCs in clinical trials represents the pharmaceutical industry’s interest in investment for research and development in this field.

Key takeaways expected from ESMO2020 for ADCs:

  • What new indications to look out for ADCs (including glioblastoma multiforme and beyond)?
  • Determining the scope for use of antibody-drug conjugates in solid tumors
  • Applying optimized HER2-testing strategies to facilitate molecular characterization of solid tumors
  • Integrating novel antibody-drug conjugate approaches into care for patients with a variety of solid tumor types
  • Recent innovations in ADC technology and much more