Therapeutic Antibodies for Cancer Treatment: Past, Present and Future

Until about 35 years ago, cancer treatment was based on three pillars – surgery, radiation, and chemotherapy – with a few exceptions. Depending on the type and stage of the tumor, these three treatment methods were used in various combinations and sequences, and over the decades, chemotherapy regimens have been continuously improved. However, almost all chemotherapeutic agents interfere with cell division in an untargeted manner – for example, by inhibiting the cell division apparatus or by damaging DNA – and therefore have a significant impact on healthy cells and tissues in the body.

In 1992, however, the advances made in genetics and molecular biology in the 20th century paid off in a spectacular fashion. Trastuzumab, a monoclonal antibody (mAb) targeting the EGFR-related protein HER2, entered phase I clinical testing in the treatment of HER2-positive breast cancer [1]. The following year saw the arrival of rituximab, an αCD20 antibody whose ability to deplete B cells proved highly successful in the treatment of lymphomas [2]. These drugs received approvals by the Federal Drug Administration (FDA) in their respective indications in 1998 and 1997, respectively [3,4].

Classic mAbs like trastuzumab are still widely used today, but over the years a number of innovations have increased the range of application and effectiveness of antibody-based oncologic therapies. In the following article, we will briefly discuss the mechanism of action of classic mAbs and how checkpoint inhibitors, antibody-drug conjugates (ADCs) and bispecific antibodies use new mechanisms to help patients with hard-to-treat cancers.

Mode of action of monoclonal antibodies

While trastuzumab and rituximab were not the first mAbs to enter the clinic (Muromonab-CD3 had been in use since 1986 in organ transplantation [5]), their success gave a huge boost to the field of oncology, leading to implementation in the treatment of most types of cancer and other rare and hard-to-treat diseases. Most mAbs target structures on the surface of cancer cells to inhibit cell growth and/or mark cancer cells as a target for cellular immune response – a mechanism called antibody-dependent cellular cytotoxicity (ADCC). Trastuzumab and rituximab fall into this category of mAbs. Other mAbs deprive growth factor receptors of their ligands, e.g. the vascular endothelial growth factor (VEGF)-binding antibody bevacizumab.

Checkpoint inhibitors

Their ability to bind to tumor antigens with high affinity and specificity made mAbs an effective tool against tumors harboring the corresponding surface markers. However, this limits their applicability to those specific cancers. Some tumors show no or insufficient expression of suitable targets, and many lose their targetable antigens over time, leading to the development of resistance. Therefore, another revolutionary approach was the development of antibodies that mobilize the immune system against tumors. Different immune checkpoints limit the activities of T-cells, including their anti-cancer activity. The two most important ones for oncology are 1) cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and 2) programmed death 1 (PD-1), which are surface proteins on T-cells, or PD-L1, a transmembrane protein that is expressed by many cancers and tumor-associated fibroblasts as a mechanism of immune evasion [6]. By binding to these proteins, antibodies like ipilimumab (αCTLA-4) and pembrolizumab (αPD-1) can significantly enhance the antitumor activity of T-cells and lead to sustained remissions in previously untreatable cancers. The greatest strength of checkpoint inhibitors is their broad applicability; the PD-1-targeted antibody pembrolizumab is approved by the FDA and the European Medicines Agency (EMA) for more than 10 indications [7]. Besides CTLA-4 and PD‑(L)1, many more targets for antibody-based checkpoint inhibition are under investigation in oncologic research. Antibodies against the TIGIT receptor, such as tiragolumab and domvanalimab, are being studied in phase III trials, but have yet to demonstrate the hoped-for efficacy [8,9]. Studies on checkpoint inhibitor combinations  and in other indications are ongoing [10]. Other targets currently being explored include LAG-3, TIM-3, VISTA and ICOS [11].

Antibody-drug conjugates (ADCs)

The primary drawback of conventional chemotherapies is their inability to distinguish between cancer cells and rapidly dividing healthy cells and tissues. The maximum tolerable dose is limited by particularly sensitive tissues such as the bone marrow and intestinal mucosa. An ADC is a monoclonal antibody covalently bound to a small molecule substance with anticancer properties. ADCs allow cytostatic and cytotoxic agents to be transported directly to cancer cells and also enable the use of agents that are not suitable for direct systemic administration due to their high toxicity [12]. Enrichment in tissues that overexpress the target structure increases efficacy while (to some degree) sparing sensitive healthy tissues. The main effect is usually achieved directly in the target cells after internalization of the ADC, but ADCs can also exert bystander effects through premature cleavage of the active substance or its release after the death of the target cell [13].

The first approved ADC was the CD33-targeting gemtuzumab ozogamicin, used for the treatment of CD33+ acute myeloid leukemia since 2000. However, ADC development really took off in the second half of the 2010s, with drugs such as polatuzumab vedotin in diffuse large B-cell lymphoma (DLBCL; 2017), trastuzumab deruxtecan in breast cancer (2019), gastric cancer (2021) and lung cancer (2022), and belantamab mafodotin in ovarian cancer (reapproved in 2025) [14]. Compared to conventional mAbs, ADCs such as trastuzumab deruxtecan can be more effective against cancers with low or ultralow expression levels of the antigen target [15]. While ADCs tend to be better tolerated by patients compared to conventional chemotherapy, some are associated with other issues, e.g. ocular toxicity [16]. Current efforts for the improvement of ADCs focus on higher specificity for their target, higher drug-to-antibody ratios, linkers with different properties and innovative (non-chemotherapy) payloads [14,17].

Bispecific and multispecific antibodies

Conventional mAbs can recruit immune cells to kill tumor cells via the ADCC mechanism. Bispecific antibodies (bsAbs), also called bispecific T-cell engagers, go one step further by binding to a tumor antigen with one arm and (typically) the T-cell surface protein CD3 with the other, thereby bridging cancer cells and T cells. This physical link avoids the need for MHC-I binding and CD28-mediated costimulation, thereby overcoming the natural tolerance of self that is not only a barrier to autoimmunity but can also prevent robust cellular responses against tumors [18]. Additionally, bsAbs promote the formation of persistent memory T-cells that can suppress tumor recurrence even after no bispecific antibodies are detectable in the patient’s body [19]. The mechanism of action of bsAbs is therefore similar to that of CAR-T cell therapies. Accordingly, they also have a similar side effect profile – in particular, attention must be paid to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) after administration [20]. Unlike CAR-T cells, bsAbs are standardized products which are available off-the-shelf.

While bsAbs have demonstrated remarkable efficacy in some hard-to-treat cancers, tumors usually develop resistance (mostly via antigen loss) and eventually recur. Novel approaches therefore focus on overcoming resistance mechanisms by combining multiple bsAbs [21], using trivalent antibodies [22], or new ways of activating T-cells, e.g. tumor antigen/CD-28 bispecifics [23].

Benefits for patients with rare cancers

Prior drug-based cancer therapies focused on the tumor’s tissue of origin. This had significant disadvantages for patients with rare types of cancer. Current efforts in oncology are increasingly moving toward biomarker- and driver oncogene-based therapies – a paradigm shift that is sometimes referred to as the “genome first” approach. From a genetics-based perspective, many rare cancers are no longer rare at all, which makes it possible to find effective treatment options from the established library of targeted antibodies and small molecule inhibitors. For example, studies show HER2 gene alterations can be found in a multitude of different cancers, raising hope for the application of HER2-targeting antibodies in all HER2-positive malignancies [24]. Furthermore, treatment success can also be achieved with the highly versatile checkpoint inhibitors in many rare types of cancers such as Merkel cell carcinoma, angiosarcoma, and some biliary tract cancers [25].

Conclusion

Antibody-based cancer therapies, together with small molecule inhibitors, form the basis for innovations in 21st century oncology. Initially developed as targeted therapies for selected tumors, they are now used in almost all oncologic indications. ADCs represent a targeted and more effective modern variant of chemotherapy, while checkpoint inhibitors are a broad acting, almost universal tool that can be used in a wide range of cancers. Finally, bi- and multi-specific T-cell engaging antibodies recruit the body’s own T cells to target cancer cells in a highly specific manner, offering a similar mode of action like CAR-T cell therapies, while keeping logistics simple due to the possibility of large-scale production.

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