HER2 is overexpressed in breast, gastric, and other solid tumors, while its expression in normal tissues is limited. Despite the clinical impact of HER2-targeted monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates (ADCs), therapeutic resistance and on-target, off-tumor toxicity remain significant challenges. Bispecific antibody T-cell engagers (TCEs) offer a novel strategy to harness the immune system for solid tumor therapy, yet previous HER2 TCEs have been hampered by safety concerns. ABP-102/CT-P72, a next-generation HER2×CD3 tetravalent bispecific antibody, is engineered to selectively target HER2-overexpressing tumor cells by reducing the affinity of its bivalent HER2 arms, thereby minimizing activity against HER2-low cells and reducing the risk of toxicity in normal tissues.
This IgG1-[L]-scFv format antibody features functionally monovalent CD3 binding, enabling controlled T-cell engagement and cytotoxicity. Preclinical studies have demonstrated that ABP-102/CT-P72 mediates T-cell activation, cytotoxicity, and cytokine release in a HER2 expression-dependent manner in vitro. In vivo, the candidate showed potent inhibition of tumor growth in HER2-overexpressing xenograft models (NCI-N87 and BT-474), with expectedly lower activity in HER2-low models (HT55). Notably, ABP-102/CT-P72 exhibited up to a two-fold increase in tumor growth inhibition compared to a biosimilar of runimotamab (BTRC-4017A / RG-6194), an experimental HER2xCD3 T cell-engaging bispecific antibody developed by Genentech/Roche for the treatment of HER2-expressing solid tumors.* Toxicology studies in cynomolgus macaques confirmed good tolerability.
The human epidermal growth factor receptor 2 (HER2) is a cell surface protein involved in cell growth and differentiation. Overexpression of HER2 is implicated in various solid tumors, notably breast and gastric cancers, and is associated with aggressive disease and poor prognosis[2][3]. While antibody-drug conjugates (ADCs) and monoclonal antibodies have improved outcomes in HER2-positive malignancies, resistance and tolerability issues remain significant challenges[4]. Bispecific T-cell engagers (TCEs) represent a new therapeutic paradigm, leveraging the immune system for targeted cytotoxicity. CT-P72/ABP-102 is a novel, dual-affinity engineered HER2×CD3 TCE designed to address these limitations.
Mechanism of Action and Design
CT-P72/ABP-102 functions as a tetravalent bispecific antibody that binds HER2 on tumor cells and CD3 on T cells, thereby facilitating immune-mediated tumor cell lysis [5]. The molecule is engineered using dual-affinity tuning to ensure strong binding to HER2-high tumor cells while minimizing engagement with HER2-low normal tissues. CD3 binding is similarly optimized for safety, reducing off-tumor activation and cytokine-related toxicity.
This selective engagement is intended to expand the therapeutic index and improve the safety profile compared with earlier-generation TCEs.
Preclinical Efficacy and Selectivity
Extensive preclinical studies have demonstrated that CT-P72/ABP-102 exhibits potent and selective anti-tumor activity in vitro and in vivo:
- In vitro cytotoxicity assays showed robust T-cell activation and cytotoxicity against HER2-high tumor cells, with markedly reduced activity against HER2-low cells, confirming high tumor selectivity.
- In vivo studies, including dual-xenograft mouse models with HER2-high (BT-474) and HER2-low (HT-55) tumors, showed that CT-P72/ABP-102 effectively suppressed tumor growth in HER2-high xenografts without significantly affecting HER2-low tumors.
- In animal models of Enhertu-resistant gastric cancer (NCI-N87/hABCG2) and breast cancer (KPL4), the candidate maintained efficacy, suggesting potential to overcome resistance to existing HER2-targeted therapies.
- Microphysiological system (MPS) experiments using patient-derived organoids confirmed T-cell infiltration and cytotoxicity in HER2-positive breast cancer, providing further translational relevance.
- ABP-102/CT-P72’s activity was up to two-fold superior in tumor growth inhibition compared to a biosimilar of runimotamab, an existing HER2×CD3 TCE[1].
Safety and Tolerability
A pivotal concern with T-cell engaging antibodies is the risk of cytokine release and off-tumor toxicity. In good laboratory practice (GLP) toxicology studies in cynomolgus monkeys, CT-P72/ABP-102 was well tolerated at doses up to 80 mg/kg, with no significant adverse events observed. The dual-affinity design appears to reduce risk to normal tissues expressing low levels of HER2, supporting a favorable safety profile.
Based on promising preclinical data, CT-P72/ABP-102 received U.S. FDA Investigational New Drug (IND) clearance in December 2025, enabling initiation of a global Phase 1 clinical trial. The study is currently enrolling patients and will evaluate safety, tolerability, and preliminary efficacy in HER2-positive solid tumors. Celltrion has announced plans to seek FDA Fast Track designation in 2026, aiming to expedite development for patients with high unmet needs.
Therapeutic Potential and Future Directions
CT-P72/ABP-102’s robust preclinical activity across multiple HER2-high tumor types—including breast, gastric, bladder, biliary tract, and colorectal cancers—suggests broad applicability. By overcoming resistance mechanisms seen with current ADCs (e.g., trastuzumab deruxtecan) and offering improved selectivity, the candidate is positioned as a potential best-in-class therapy. The parallel development of additional multispecific antibodies and ADCs (e.g., CT-P70, CT-P71, CT-P73) highlights Celltrion’s commitment to expanding its oncology pipeline.[6]
CT-P72/ABP-102 represents a significant advance in HER2-targeted immunotherapy, offering potent and selective anti-tumor activity with a favorable safety profile in preclinical models. Ongoing clinical trials will determine its impact on HER2-positive solid tumors, including those resistant to current standards of care. If successful, CT-P72/ABP-102 could redefine the therapeutic landscape for patients with HER2-driven malignancies.
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Note: * In 2025, despite promising early data from the combination therapy, Genentech/Roche removed RG6194/runimotamab, which was in development from its clinical development pipeline. Phase I trials evaluating runimotamab (NCT03448042) for HER2-expressing solid tumors, including metastatic breast cancer and gastric cancer, were underway. The trial remains listed as active, with an expected primary completion date in November 2027.
Prescribing information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
References
[1] Pelzek A, Murphy S, Ebtehaj S, et al. ABP-102/CT-P72: a novel HER2 x CD3 T cell engager with selective activity for HER2-overexpressing tumors and reduced activity on cells with normal HER2 expression levels [abstract]. Cancer Res 2025;85(8_Suppl_2):ND04. Online. Last accesses in June 2026.
[2] Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707-12. doi: 10.1126/science.2470152. PMID: 2470152.
[3] Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008 Sep;19(9):1523-9. doi: 10.1093/annonc/mdn169. Epub 2008 Apr 25. PMID: 18441328.
[4] Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I; DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):610-621. doi: 10.1056/NEJMoa1914510. Epub 2019 Dec 11. PMID: 31825192; PMCID: PMC7458671.
[5] CT-P72/ABP-102: A dual-affinity engineered HER2/CD3 tetravalent bispecific antibody with potential to overcome therapeutic barriers in HER2 high tumors with distinct potency, safety, and selectivity. Poster presented at SITC 2025 Annual Meeting.
[6] Celltrion Confirms Efficacy of Next-Generation Multispecific Antibody Drug Candidate. Seoul Economic Daily. Jun 14, 2026.
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