Overview of ADC Combination Therapies

Antibody-drug conjugates (ADCs) have emerged as a promising class of treatments in the evolving field of cancer treatment. ADCs combine the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, providing a novel approach to targeted therapy. ADCs show great promise in the fight against cancer and have the potential to be game-changers for targeted therapies across a range of non-oncology indications.

What is Antibody-Drug Conjugate?

ADCs represent an important class of cancer therapies that have revolutionized the treatment paradigm for solid tumors. To date, many ongoing studies of ADCs in combination with various anticancer drugs, including chemotherapy, molecularly targeted drugs, and immunotherapy, are being conducted rigorously in preclinical research and clinical trial settings. Over the past decade, ADCs have become a transformative treatment modality for a wide range of solid tumors and hematological malignancies. ADCs are antibody-based macromolecular complexes containing three main components: antibody, linker, and payload.

• Monoclonal antibodies, which bind to antigens primarily expressed on the surface of tumor cells, provide specificity for targeting tumor cells;
• The linker prevents premature release of the payload into the bloodstream and instead releases it into the tumor cells;
• The cytotoxic payloads that trigger tumor cell death by targeting key components such as DNA, microtubules, and topoisomerases.

ADC cytotoxicity involves a series of sequential stages: 1) binding of antibody to antigen, 2) internalization of ADC-antigen complex, 3) degradation of ADC in lysosomes, 4) release of payload in the cytoplasm, 5) its interaction with the antigen, 6) possible release of a portion of the payload into the extracellular environment, 7) subsequent bystander effect, internalization by neighboring cells in the tumor microenvironment.

Fig. 1. Structure and mechanism of action of conventional ADCs (J Hematol Oncol. 2024, 17: 1).

At present, the regulatory authorities have approved the combination of ADC and chemotherapy/chemical immunotherapy for hematological malignancies, and the FDA has also awarded the breakthrough therapy identification of enfortumab vedotin and pembrolizumab. The most attractive drugs in combination with ADCs are those partners that have an additive or synergistic effect on tumor cells or their microenvironment without unacceptable overlapping toxicity. The combination of anti-angiogenic drugs, HER2 targeted drugs, DNA damage response agents and immune checkpoint inhibitors (ICIs) is currently an active research direction.

Our Antibody-Drug Conjugates (ADCs)

ADC Combination Therapy

To date, 8 ADCs have been approved for use in solid tumors with different indications. In the field of cancer treatment, it is generally accepted that the likelihood of achieving complete remission and cure can often be improved by combining therapeutic agents that act through different mechanisms of action, especially when dealing with the complexity of tumor heterogeneity. Combinations of ADCs with various other types of anticancer drugs, such as chemotherapy, radiotherapy, endocrine therapy, targeted molecular agents, and immunotherapy, are being explored in preclinical models and clinical trials.

• Chemotherapy: By upregulating tumor cell surface antigens, it causes cell cycle arrest and inhibits DNA repair.
• Targeted drugs: The synergistic use of ADCs and targeted drugs can block multiple oncogenic pathways at the same time, or double block specific pathways to more effectively inhibit downstream signaling.
• Immunotherapy: ADC maintains the immune system of the tumor microenvironment in an activated state through different immune mechanisms, including macrophage reprogramming, T memory cell production, induction of increased PD-L1 expression, and activation of dendritic cells and T cells. These changes may improve the efficacy of immunotherapies used in combination with anti-PD1/PD-L1 antibodies, while ADCs can also be designed to target specific elements of the tumor microenvironment, such as fibroblasts.

Fig. 2. ADC-based combination therapies (Trends Cancer. 2023, 9(4): 339-354).

ADC Combined with Chemotherapy

ADC allows chemotherapy drugs to be more accurately targeted. The special structure of an ADC, which includes an antibody and a linked drug, allows the drug to remain inactive while circulating in the body until it is released and activated in a target cell. Targeted release of cytotoxic chemotherapy drugs in the tumor microenvironment improves the anti-tumor effect and reduces systemic toxicity. Therefore, ADC provides greater therapeutic opportunities than traditional systemic chemotherapy. This accurate targeting mechanism makes treatment more targeted, reduces adverse effects on healthy tissue, and improves the safety and effectiveness of treatment. Chemotherapy and ADCs have been reported to show synergistic effects, covering targeting or modulating tumor cell surface antigen expression at different stages of the cell cycle.

• Blockers targeting the cell cycle

Many chemotherapy drugs, such as antimetabolites, platinum compounds, and topoisomerase inhibitors, are DNA damaging agents. They target the S phase of the cell cycle and induce G2/M phase arrest, forming effective combinations with ADCs containing microtubule-disrupting payloads to target the G2/M phase of the cell cycle. This concept combines carboplatin with mituximab soraftansine (targeting folate receptor α with DM4), anelizumab soraftansine (targeting mesothelin with DM4), or rubelumab Tazewellibulin (targeting folate receptor alpha with SC239) has been shown to be effective in combination, particularly in preclinical ovarian cancer.

• Improving surface antigen expression

The choice of chemotherapeutic agent may affect the levels of surface antigens targeted by the ADC. For example, gemcitabine can upregulate HER2 expression on pancreatic cancer cells, mainly in the G2/M phase, making it more effective in G1 and early S phase cells. This means that gemcitabine is more likely to be effectively combined with trastuzumab emtansine (T-DM1, which targets HER2 with a DM1 payload), helping to improve efficacy against pancreatic ductal adenocarcinoma cells.

• Design dosing time

The administration time may be related to the drug combination design. Tubulin polymerization is a key component of the endocytosis mechanism of ADC. DNA damage-mediated G2/M phase arrest may take some time to sensitize microtubule disruptors. This was well demonstrated by studies in colon cancer, lung cancer and breast cancer models, and continuous administration of SGN-15 (Lewis Y antigen-doxorubicin) and paclitaxel caused more DNA fragmentation than simultaneous administration. This observation shows that adjusting the administration time, especially the delayed administration of DNA damage agents after anti-microtubule drugs, may improve the therapeutic effect.

• Overlapping toxicity

ADC is essentially chemotherapy, so the improvement of the efficacy of the combined regimen is often hindered by unacceptable toxicity. The main toxicity is driven by the metabolites of cytotoxic payloads, which must be carefully considered in the design of combination strategies. These toxicities include peripheral neuropathy caused by MMAE and DM1 derivatives, ocular toxicity caused by MMAF and DM4, gastrointestinal effects of DM1 or topoisomerase inhibitors, or hepatotoxicity caused by calicheamicin derivatives, and almost universal neutropenia and thrombocytopenia.

ADC Combined with Targeted Therapy

ADCs improve the therapeutic index and enhance activity against specific tumor populations compared to standard chemotherapy, making them an ideal partner for targeted agents. One can envision various combinatorial strategies to overcome therapeutic resistance and clonal heterogeneity, elicit stronger inhibition of oncogene-dependent signaling pathways, increase surface antigen availability and sensitize low antigen-expressing tumors, and modulate the tumor microenvironment.

• Enhancing cellular uptake and anti-tumor activity

The large molecular size of ADC limits its distribution in tumor tissues, resulting in poor efficacy. Barriers to ADC delivery include the blood-tumor barrier (physical barrier) and the binding site barrier (biological barrier). In the blood-tumor barrier, solid tumors have immature and disorganized blood vessels, resulting in poor blood flow and hypoxia. The use of anti-angiogenic antibodies such as bevacizumab can modulate angiogenesis and improve ADC delivery.

• Overcome binding site barriers

The binding site barrier is a biological barrier in the tumor vasculature region that limits the efficacy of high-affinity antibodies. Improving antibody distribution in solid tumors through transient competitive inhibition is one strategy to overcome binding site barriers.

• Upregulate surface antigens and overcome intratumoral heterogeneity and drug resistance

Intratumoral heterogeneity and drug resistance are key factors in treatment failure. Monoclonal antibodies and tyrosine kinase inhibitors (TKIs) may provide greater selectivity in combination therapy. The combined use of ADCs and TKIs may overcome ADC resistance.

• Integrated lethality and joint targeting

Synthetic lethality is a promising therapeutic strategy for tumors with defects in DNA homologous recombination repair pathways. A subset of ADCs that inhibit TOPO 1 have shown clinical efficacy. By combining TOPO 1 inhibitors and PARP inhibitors, double-stranded DNA breaks can accumulate in cells, leading to cell apoptosis and death.

ADC Combined with Immunotherapy

There is growing evidence that ADCs are sensitive to the effectiveness of immunotherapeutic drugs. Combining immunotherapy with ADCs is a current trend in clinical practice, and preliminary results from a large number of preclinical studies and early clinical trials have shown improved anti-tumor effects. The mechanism of ADC combined immunotherapy has many aspects, including the effector function mediated by the Fc region of the antibody, the initiation of immunogenic cell death (ICD), the maturation of dendritic cells (DC), the enhancement of T-cell infiltration, the enhancement of immune memory, and the expression of immunomodulatory proteins (such as PD-L1) and major histocompatibility complex (MHC).

• Fc region-mediated effector functions

Fc-mediated effector function plays a key role in the design of ADCs. The Fc region of an antibody regulates the circulation time of the antibody in the bloodstream by interacting with immune cells, and affects antibody-dependent cell-mediated cytotoxicity, Phagocytosis and complement-dependent cytotoxicity. Different IgG antibody subclasses have different effects on the efficacy of ADCs, with IgG1 being the most commonly used ADC type subclass because of its longer half-life and stronger effector function. When designing ADCs, engineering the Fc region can modulate immune system engagement, for example by producing afucosylated IgG to enhance antibody-dependent cell-mediated cytotoxicity. However, considerations of immune effects and potential toxicity need to be balanced.

• Immunogenic cell death (ICD)

Immunogenic cell death (ICD) is the death of cancer cells that activates the immune system. Most cytotoxic payloads used in ADCs exhibit the ability to activate immune cells, improve anti-tumor efficacy, and synergistically enhance the effects of immune checkpoint inhibitors. This effect may involve the drug's ability to induce ICD and establish immune memory. ADCs can be designed to modulate their ability to activate and mature DCs by introducing mutations in the payload. Direct activation and maturation of dendritic cells

• Direct activation and maturation of dendritic cells

ADCs can also directly activate and mature dendritic cells, prompting them to play a key role in tumor immunity. By regulating the function of DCs, ADCs help overcome immune suppression and improve the immune system's ability to respond to tumors. Clinical trials combining ADCs and immune checkpoint inhibitors have shown synergistic effects, improving treatment efficacy.

ADCs Cytotoxins and Linkers

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Overview of ADC Combination Therapies

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