Faculty

​Introduction to Antibody-Drug Conjugates (ADCs)

​A typical drug conjugate is formed by chemically attaching a payload (or small molecule toxin) to a targeting agent (such as an antibody) via a linker. The targeting agent transports the payload specifically into tumor cells to inhibit tumor growth. Clinically, the most common type of drug conjugates are antibody-drug conjugates (ADCs), of which there are now 13 with approval from the US Food and Drug Administration (FDA) for different oncological indications. Gemtuzumab ozogamicin was the first FDA-approved ADC, which gained clinical use in 2000 for CD33+ acute myeloid leukemia. The second ADC, brentuximab vedotin, was approved in 2011 to treat Hodgkin’s lymphoma. From 2013 to 2017, two ADCs (trastuzumab emtansine, and inotuzumab ozogamicin) were approved, and from 2019 to 2022, nine additional ADCs arrived. Exciting preclinical research on ADCs and other drug conjugates is growing, with the hope of yielding other effective clinical agents.

​References:
1. Dumontet et al. Nat Rev Drug Discov. 2023; Jin et al. Pharmacological Reviews July 2022; Hafeez et al. Molecules 2020
2. Dumontet et al. Nat Rev Drug Discov. 2023
3. Dumontet et al. Nat Rev Drug Discov. 2023; Jin et al. Pharmacological Reviews July 2022

​ADCs Across a Broad Range of Targets

Currently, the indications for ADC drugs are all focused on the oncology field. There are currently 13 approved ADCs marketed worldwide, including six that target six different antigens (CD33, CD30, CD22, CD79b, B cell maturation antigen (BCMA, also known as TNFRSF17) and CD19) in haematological malignancies, and seven targeting five different antigens (HER2, nectin-4, tumour-associated calcium signal transducer 2 (TACSTD2, also known as TROP2), tissue factor and folate receptor alpha (FRα) in solid tumours. Despite some ADC research interruptions, 76 biomarker targets are still being investigated, among which the common solid tumor targets developed include 28 targeting HER2, 14 targeting CLDN18.2 and 12 targeting Trop-2. Significant progress has been made in ADC development, and future research will focus on new targets, different cytotoxic agents, different molecular structures, and different indications to improve the treatment of patients with conventional chemotherapy.

References:
1. Dumontet et al. Nat Rev Drug Discov. 2023; Global Oncology Trends 2023 OUTLOOK TO 2027; Biopharma PEG website
2. Biopharma PEG website
3. Global Oncology Trends 2023 OUTLOOK TO 2027

ADCs in Lung Cancer

Currently, early-phase trials of ADCs in non–small cell lung cancer (NSCLC) are rapidly gaining ground, with promising results targeting HER2 (human epidermal growth factor 2), HER3, TROP2 (trophoblast cell surface antigen 2), MET, CEACAM5 (carcinoembryonic antigen–related cell adhesion molecule 5), and PTK7 (tyrosine protein kinase–like 7). Unfortunately, in small cell lung cancer (SCLC), trials targeting the ubiquitous DLL3 (delta-like ligand 3) protein have failed to show clinically relevant results, despite significant toxicity. Trastuzumab Deruxtecan (also known as DS-8201a or T-DXd) an ADC directed at HER2 recently became the first ADC to receive FDA approval in lung cancer, on the basis of its activity in tumors with HER2 mutations, demonstrated in the Destiny-Lung01 and Lung02 trials. Therefore, there is a need to focus on the current and upcoming development of ADCs in metastatic lung cancer and to understand the current state of ADCs in ongoing trials in NSCLC and SCLC. In most cases, phase III trials are ongoing, with readouts expected in the upcoming years.

References:
1. Rosner et al. 2023 ASCO EDUCATIONAL BOOK; Merle et al. The Cancer Journal November 2022
2. DAVA Hawaii Lung Summit 2023 & 2022; Dumontet et al. Nat Rev Drug Discov. 2023; Merle et al. The Cancer Journal November 2022

​ADCs in Breast Cancer

HER2-positive cancers, including both breast cancers and other solid tumour types, currently make up a large share of all patients receiving ADCs. Because HER2 is internalized upon binding by an antibody, the first anti-HER2 ADC was developed using the already approved and widely administered ‘naked’ antibody, trastuzumab. Currently, two HER-directed ADCs have received FDA approval for HER2-positive metastatic breast cancer patients: ado-trastuzumab emtansine, and trastuzumab deruxtecan. Very recently, sacituzumab govitecan has received FDA approval for HER2-negative metastatic breast cancer. There are also several ADC drugs in different phases of clinical trial for breast cancer patients. Clinical progress with ADCs for the targeted therapy of breast cancer have shown promise. Off-target toxicities and drug resistance to ADC-based therapy have hampered effective therapy development due to the intracellular mechanism of action and limited antigen expression on breast tumors. Novel ADC drugs may deliver potent cytotoxic agents to breast tumor cells with reduced off-target effects, which may overcome difficulties related to delivery efficiency and enhance the therapeutic efficacy of cytotoxic cancer drugs for breast cancer therapy.

​References:
1. Dumontet et al. Nat Rev Drug Discov. 2023; Abdus Subhan et al. Pharmaceutics 2023, 15, 1242
2. DAVA Hawaii Breast Summit 2023; Dumontet et al. Nat Rev Drug Discov. 2023; Abdus Subhan et al. Pharmaceutics 2023, 15, 1242

ADCs in Urothelial Carcinoma

Significant progress has been achieved over the last decades in understanding the biology and mechanisms of tumor progression in urothelial carcinoma (UC). Although the therapeutic landscape has dramatically changed in recent years with the introduction of immune checkpoint inhibitors, advanced UC is still associated with rapidly progressing disease and poor survival. The increasing knowledge of the pathogenesis and molecular pathways underlying cancer development and progression is leading the introduction of target therapies, such as the recently approved FGFR inhibitor Erdafitinib, or the anti-nectin 4 antibody drug-conjugate Enfortumab vedotin. Antibody drug conjugates represent an innovative therapeutic approach that allows the combination of a target-specific monoclonal antibody covalently conjugated via a linker to a cytotoxic agent (payload). UC is a perfect candidate for this therapeutic approach since it is particularly enriched in antigen expression on its surface and each specific antigen can represent a potential therapeutic target.

References:
1. Ungaro et al. Cells 2022, 11, 803

​Bispecific in Lung Cancer

Amivantamab is the only EGFR x cMET bispecific antibody approved for EGFR exon 20–mutated NSCLC, following platinum-based chemotherapy, Amivantamab is presently being considered for various subtypes of EGFR-mutated and MET-altered lung cancers. A number of bispecifics, such as tarlatamab, ivonescimab, KN046, M7824, SI-B001, and AK112, have entered phase-III clinical trials for lung cancer treatment. At present, the MOAs of bsAbs in the treatment of lung cancer mainly include the following three categories: bridging immune cells with tumor cells for redirected cytotoxicity, dual tumor targeting, and targeting dual immunomodulatory molecules to promote immune responses. Current BsAb development in lung cancer mainly focuses on the targets HER2/ HER3, EGFR, MET, and PD-1/ CTLA-4. Currently there are a number of specifics in phase II and early-stage development in lung cancer. Bispecifics such as AFM24, and MCLA-129​ have shown promising results in the phase 1 trials.​ AFM24 activates NK cells and directs them to cancer cells expressing EGFR which increases their capability to selectively kill cancer cells. Two patients with bowel cancer and lung cancer after receiving the AFM24, their cancer shrank or stopped growing for >3 months. (ASCO 2022). REGN5093 is a MET-targeting human IgG4p bispecific antibody currently in the early stage of enrollment. Preclinical study of REGN5093 has exhibited significant efficacy on MET-overexpressed TKI-naïve EGFR-mutant NSCLC cells.

References:
1. Reyes et al, Cancers (Basel), 2023 2. Gadea et al, ASCO, 2022; Oh et al, Clin Cancer Res. 2023

​Bispecific in Breast Cancer

BsAbs targeting human epidermal growth factor receptor 2 (HER2) have shown the ability to redirect immune cells to HER2-positive BCa cells, resulting in effective tumor cell killing. Moreover, targeting the PD-1/PD-L1 pathway by BsAbs has demonstrated promising outcomes in overcoming immunosuppression and enhancing immune-mediated tumor clearance. Since the first bispecific antibody (Catumaxomab) was launched in 2009, nine bsAbs (seven for tumors) were approved for marketing, and five of them are coming to market in 2021 and 2022.

​Bispecific in Genitourinary Cancer

Bispecific antibodies are under development for prostate targeting PSMA, STEAP1, DLL3. PSMA is the most prominent and widely used tumor-associated antigen (TAA) in Prostate cancer. Other targets evaluated for BsAbs are STEAP1, ENPP3, HER2, CD155.

References:
1. Zhang et al, Cancer Biol Med. 2023; Heitmann et al Cancer(Basel), 2021; Clinicaltrial.gov

​Next Generation Emerging ADCs (Phase 1 Drugs)

Antibody-drug conjugates (ADCs) embody a simple, but elegant, vision for cancer therapy—the delivery of a potent cytotoxic agent to tumor cells with minimal damage to normal cells—so-called smart chemo. Since the first ADC, Mylotarg® (gemtuzumab ozogamicin), was approved in 2000 by the US Food and Drug Administration (FDA), there have been 12 ADCs received market approval so far worldwide. The most successful application for solid tumors has been in breast cancer, with ADCs becoming the standard of care across traditional human epidermal growth factor receptor 2 (HER2)+, hormone receptor+ (HR+) and triple-negative disease subtypes. Moreover, the improved features and gains in potency with the development of ADCs have expanded the treatment-eligible population to those with low/heterogeneous expression of the target antigen on the tumor with trastuzumab deruxtecan or in the case of sacituzumab govitecan, agnostic to target expression. As more ADCs are included in the treatment armamentarium, mechanisms of resistance need to be studied and understood for optimal sequencing. Modifying the payload to use immune-stimulating agents or combination therapies with immunotherapy and other effective targeted therapies may further extend the utility of these agents in the treatment of cancer. More than 50 different known antigens have been used as targets in ADCs currently in preclinical or clinical development. Moreover, over 100 ADC candidates have been investigated in clinical stages at present. This kind of new anti-cancer drugs, known as “biological missiles”, is leading a new era of targeted cancer therapy. The list of phase 1 emerging ADC drugs are listed here and will be discussed in this session.

References:
1. Shastry et al. ASCO EDUCATIONAL BOOK 2023; Fu et al. Signal Transduction and Targeted Therapy 2022; Hafeez et al. Molecules 2020
2. Hafeez et al. Molecules 2020
3. Dumontet et al. Nat Rev Drug Discov. 2023

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