{
  "abstract": "Background Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancers, and breakthrough HER2-targeted therapeutic agents, including antibody-drug conjugates (ADCs), have expanded treatment options for patients. However, despite clinical success, treatment with ADCs can result in safety issues and/or resistance due to drug efflux and target-associated mechanisms. T Cell Engagers (TCEs) have shown promising anti-tumor activity in solid tumor indications, but their clinical application has been challenged by significant toxicity. CT-P72/ABP-102 is a tetravalent bispecific HER2 and CD3 T-cell engager engineered with dual affinity-tuned binding to HER2 and CD3 to increase tumor selectivity and reduce off-target effects, thereby lowering the risk of safety concerns, and has potent anti-tumor activity in multiple in-vivo models, including an Enhertu-resistant model.Methods To assess target binding specificity, we evaluated cellular binding affinities of CT-P72/ABP-102 with ELISA, SPR analysis, and flow cytometry. We assessed the biologic activity of CT-P72/ABP-102 with cellular cytotoxicity, cytokine release, and T- cell activation assays using human PBMCs (hPBMCs). In-vivo efficacy was assessed in three murine models with hPBMCs: a HER2-expressing Enhertu-resistant gastric cancer (NCI-N87/hABCG2), a HER2-overexpressing (KPL4) xenograft tumor, and a dual xenograft of HER2-high BT-474 and HER2-low HT-55 cancer cells. Safety of CT-P72/ABP-102 was assessed in a GLP toxicity study conducted in cynomolgus monkeys.Results CT-P72/ABP-102 bound specifically to HER2 among the HER1-4 family and to CD3, showed cross-reactivity with cynomolgus macaque HER2 and CD3, and exhibited lower binding to both HER2 and CD3 compared to its parental antibody. CT-P72/ABP-102 demonstrated activity in T-cell activation, PBMC-mediated cytotoxicity, and cytokine release experiments comparable to the parental bispecific antibody with HER2 high-expressing tumor target cells but reduced with HER2-low tumor target cells. In vivo, in the BT-474/HT-55 dual xenograft study CT-P72/ABP-102 inhibited the growth of HER2-high BT-474 tumors but showed reduced activity against HER2-low HT-55 tumors (figure 1), demonstrating the selectivity of CT-P72/ABP-102 for high HER2 tumors over low HER2 normal tissues. The anti-tumor efficacy of CT-P72/ABP-102 has also been demonstrated in a cell line-derived xenograft (CDX) mouse model established with human breast cancer cell line (KPL-4) and in an Enhertu-resistant gastric cancer cell line in hPBMC-engrafted immunodeficient mice (figure 2). CT-P72/ABP-102 was well tolerated in 4-week repeated-dose toxicity study with 4-week recovery period in cynomolgus monkeys, being well tolerated up to the highest dose (80mg/kg) tested.Conclusions CT-P72/ABP-102 effectively addressed key limitations of current HER2-targeted therapies by combining potent, selective anti-tumor activity with a favorable safety profile.Abstract 967 Figure 1Anti-tumor activity of CT-P72/ABP-102 in a dual xenograft (HER2 high-expressing BT 474 and HER2 low-expressing HT-55) model in immunodeficient C NKG mice engrafted with hPBMCs (n=3/group). Note: Data points represent group mean; error bars represent standard error of the mean (SEM). The arrowheads indicate the time points of administration of the test articles. One-way ANOVA with Dunnett’s post-hoc analysis was performed to compare results to the control group up to Day 28. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001Abstract 967 Figure 2Anti-tumor activity of CT-P72/ABP-102 in an Enhertu-resistant NCI-N87/hABCG2 xenograft model in immunodeficient NOG Mice, engrafted with hPBMCs (n=5/group). Note: Data points represent group mean; error bars represent standard error of the mean (SEM). The arrowheads indicate the time points of administration of the test articles. . One-way ANOVA with Dunnett’s post-hoc analysis was performed to compare results to the control group up to Day 28. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001",
  "authors": [
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Hyunkyu Choi"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Bobin Kang"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Bokhyeon Im"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Juhyung Seok"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Jieun Lee"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Riri Kwon"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Ji-Seon Kang"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Bo Ryeong Lee"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Jungsun Ahn"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Eun Yeong Shim"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Yeon Jung Kim"
    },
    {
      "affiliations": [
        "Celltrion Inc., Incheon, Republic of Korea"
      ],
      "name": "Jiyoung Shin"
    },
    {
      "affiliations": [
        "Abpro Corporation, Woburn, MA, USA"
      ],
      "name": "Adam J Pelzek"
    },
    {
      "affiliations": [
        "Abpro Corporation, Woburn, MA, USA"
      ],
      "name": "Shaun P Murphy"
    }
  ],
  "title": "967 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",
  "uid": "24b399a7-d521-5603-875b-64757f728790"
}