A Reflection on the Evolution of Antibody‐Based Therapies in Oncology: Trastuzumab as an Exemplar—Commentary on Dijkers <i>et al</i>.

Since the first description of hybridoma cells capable of producing monoclonal antibodies (mAbs) 50 years ago, remarkable progress has been made in the development of antibody-based therapies in oncology. Featured in this issue of CPT is an article first published in 2010 describing 89Zr-trastuzumab for immuno-positron emission tomography (PET) imaging. This commentary places the development of HER2-targeted agents within the greater context of antibody-based development in oncology and the accompanying evolution of clinical pharmacology. The year 2025 marks the 50th anniversary of Köhler and Milstein's publication reporting the generation of hybridoma cell lines capable of producing mAb.1 Not only has this discovery enabled scientific progress across the spectrum of biomedical research, but the impact on clinical pharmacology and therapeutics has been remarkable. In 1980, Nadler et al. published a case report detailing the transient activity of a murine mAb targeting a lymphoma-associated antigen.2 Antibody-based therapies have subsequently evolved from murine mAbs to chimeric mAbs to humanized mAbs to fully human mAbs, radiolabeled antibodies, antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs) and bispecific antibodies (BsAbs), amongst others. While many of the mAbs have targeted tumor-specific antigens, others have been more directly immunomodulatory in nature (e.g., checkpoint inhibitors), yielding impressive results in previously difficult-to-treat malignancies (e.g., melanoma, renal cell carcinoma). A 2022 publication reported that the Umabs Antibody Therapies Database listed 162 antibody therapies that had been approved by at least one regulatory agency (not including biosimilar, diagnostic and veterinary antibodies).3 These 162 antibody therapies encompassed 91 drug targets and included 115 canonical antibodies, 14 ADCs, 7 BsAbs, 8 antibody fragments, 3 radiolabeled antibodies, 1 antibody-conjugate immunotoxin, 2 immunoconjugates, and 12 Fc-Fusion proteins.3 The field of cancer has been most prominently impacted by the development of mAb-based therapies, with 66 antibody therapeutics granted a first approval for a cancer indication in the United States or the European Union between 1997 and 2024.4 Not included in these totals are therapies such as chimeric antigen receptor (CAR) T-cell products which include an antibody fragment in the CAR construct. Figure 1 highlights some of the major events over the past 50 years that have transformed the cancer therapeutic landscape from an antibody-based perspective. The first humanized mAb to receive FDA approval for a solid tumor indication was trastuzumab in 1998. Trastuzumab targets the extracellular domain of human epidermal growth factor receptor 2 protein (HER-2) and is thought to induce cell death through multiple mechanisms of action, including attenuation of signal transduction pathways downstream of HER2, induction of antibody-dependent cellular cytotoxicity (ADCC) and prevention of HER2 shedding. Trastuzumab was first approved for the treatment of HER2-positive metastatic breast cancer and then later approved in the adjuvant setting. There has subsequently been a slew of HER2-targeting antibody-based therapies approved for the treatment of HER2-positive breast cancer, including another mAb (pertuzumab, which binds to a different extracellular domain of HER2, blocking ligand-dependent heterodimerization with HER1, HER3, and HER4, and is only approved in combination with trastuzumab), a chimeric Fc-engineered mAb (margetuximab, which induces ADCC and is approved for use in combination with chemotherapy) and two ADCs (Fam-trastuzumab deruxtecan (T-DXd) and Ado-trastuzumab emtansine (T-DM1)). In addition, multiple tyrosine kinase inhibitors (TKIs) have been approved: lapatinib targets EGF1 and HER2, neratinib is an irreversible pan-HER inhibitor, and tucatinib targets HER2. There has also been significant interest in the development of radiolabeled derivatives of trastuzumab, representative of the emerging field of radiotheranostics.5 The article chosen to highlight the 2010–2019 era of Clinical Pharmacology & Therapeutics was first published in 2010 by Dijkers et al.6 This manuscript reported the results of a feasibility study in which patients with HER2-positive metastatic breast cancer received a dose of 89Zr-trastuzumab followed by PET imaging. This built upon prior work demonstrating that 111In-trastuzumab could identify HER2-positive lesions that were previously undetected using conventional imaging.7 The advent of 89Zr-labeled antibodies for clinical immunoPET imaging enabled the use of a positron-emitting radiolabel with a longer half-life (78.4 hours), permitting imaging up to 1 week after injection. Dijkers et al. demonstrated accumulation of the 89Zr-trastuzumab in liver, lung, bone, and brain metastases. Although not all of the previously known lesions were identified with 89Zr-trastuzumab, in some cases, immunoPET identified new lesions.6 While immunoPET imaging with 89Zr-trastuzumab has not yet entered into clinical practice, research in this space has continued. Bensch et al. explored whether 89Zr-trastuzumab PET could be used to support clinical decision-making in cases where there was uncertainty about the HER2 status in patients with breast cancer.8 Although the outcomes of this study were subjective in that they were primarily related to whether treating physicians thought the imaging results improved diagnostic understanding or informed choice of therapy, this work did support the hypothesis that 89Zr-trastuzumab PET could be used as a diagnostic tool. Other groups have explored alternative radiolabels or mAbs for HER2-targeted immunoPET applications, including 89Zr-pertuzumab9 and 64Cu-DOTA-trastuzumab.10 IMPACT-MBC (NCT01957332), a prospective multicenter observational cohort study, was initiated in 2013 in the Netherlands and is anticipated to be completed in 2027. The primary objective of this study is to evaluate the clinical utility of experimental PET scans (including 89Zr-trastuzumab PET) in the setting of metastatic breast cancer at first presentation and will hopefully shed light on whether the use of 89Zr-trastuzumab PET should be integrated into the care of patients with HER2-positive disease. In many ways, trastuzumab and the subsequent development of other HER2-targeting antibody-based therapies are illustrative of the field as a whole. What began as single-agent mAb therapy for metastatic HER2-positive breast cancer evolved into combination-based therapies (e.g., with traditional cytotoxic agents, hormonal agents, other anti-HER2 mAb, or anti-HER2 TKIs). From there came the understanding that therapies could be target-specific, but tissue agnostic and trastuzumab is now approved for the treatment of other HER2-positive malignancies such as colorectal cancer, endometrial cancer, biliary cancer, and gastric cancer. The development of mAbs linked to toxins (i.e., the ADCs) provided an innovative way of selectively delivering cytotoxic therapy to tumor cells of interest. In fact, the first ADC to gain FDA approval for a solid tumor indication was the trastuzumab-based T-DM1 in 2013, which retains the trastuzumab-mediated actions against HER2-expressing cells while also enabling targeted delivery of the anti-microtubule agent emtansine. The first HER2 × HER3 BsAb (zenocutuzumab) was approved for pancreatic adenocarcinoma and non-small cell lung cancer harboring neuregulin 1 (NRG1) gene fusions in 2024. This agent has been referred to as having a “dock and block” mechanism whereby the HER2-targeting arm docks the antibody, providing a high local concentration and positioning the HER3-targeting arm to block binding of NRG1 to HER3, resulting in the prevention of phosphorylation of the cytoplasmic domain of HER3 and downstream signaling.11 CAR T-cell therapies, which rely on the external domain of the construct containing a scFv domain to recognize the target tumor antigen of interest, have proven to be truly groundbreaking for a variety of hematological malignancies. The number of CAR T trials for solid tumors is continuing to grow. While an initial attempt at a HER2 CAR T based on trastuzumab resulted in the study terminating after the first patient experienced respiratory distress shortly after infusion resulting in death within 1 week,12 alternative approaches such as TRAIL-R2 and HER2 bispecific CAR T-cells are being pursued (NCT06251544). The incredible therapeutic successes achieved during the evolution of antibody-based therapies in oncology over the last several decades have brought with them a myriad of new challenges for the field of clinical pharmacology. It became evident that traditional pharmacokinetic (PK) modeling and dose–response determinations that were established in the era of small molecule drugs required adjustments in the era of antibody-based therapies. Target engagements now need to be considered in the setting of multiple targets on different cell types (e.g., the tumor antigen on tumor cells and CD3 on T cells), and traditional maximum tolerated dose determinations are no longer appropriate (as recognized by the FDA's Project Optimus initiative). Recent perspectives for bispecific-based therapies13, 14 and ADCs15 outline the complexities associated with determining first-in-human dosing, assessment of safety, selection of recommended phase 2 dose, evaluation of immunogenicity, and establishment of appropriate biomarkers. The biosimilar market is a burgeoning market (e.g., there are currently six trastuzumab biosimilars available in the United States) and with that has come new regulatory challenges for the field.16 Molecularly targeted therapies have enabled the development of biomarker-driven clinical trials and approvals.17, 18 Furthermore, quantitative systems pharmacology has risen to the challenge of integrating virtual patients and trials into the development platforms of immuno-oncology therapies.19 In conclusion, the identification of HER2 as a potential therapeutic target for breast cancer, with the subsequent journey from trastuzumab to HER2-targeting tyrosine kinase inhibitors, radiolabeled antibodies, ADCs, BsAbs, and CAR T cells, is illustrative of the remarkable progress that has been achieved in cancer therapy, particularly with respect to antibody-based therapies. Currently, the armamentarium for nearly all malignancies includes therapeutic options derived from antibody-based therapies. Along the way, the contributions of clinical pharmacology in establishing new frameworks for PK-PD determinations, population PK modeling, quantitative systems pharmacology, and trial design have been instrumental to therapeutic successes. The further expansion of molecular subtyping of malignancies, development of personalized therapies, improved understanding of mechanisms of resistance to immuno-oncology therapies, and future breakthroughs in bioengineering of antibody- and cellular-based therapies ensure that those involved in clinical pharmacology research will remain at the forefront of discovery. No funding was received for this work. SAH has served as a consultant for Janssen, Sanofi, and Takeda (not related to this work). As an Associate Editor for Clinical Pharmacology & Therapeutics, Sarah A. Holstein was not involved in the review or decision process for this paper.