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  • American Association for Cancer Research (AACR)  (3)
  • Park, Yun-Hee  (3)
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  • American Association for Cancer Research (AACR)  (3)
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  • 1
    Online Resource
    Online Resource
    Abstract 6296: Preclinical study of a novel anti-CLEC12A antibody-drug conjugate with a glucuronide-protected pyrrolobenzodiazepine payload
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6296-6296
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6296-6296
    Abstract: C-type lectin domain family 12 member A (CLEC12A, CLL-1) is a single-pass transmembrane protein of 265 amino acids that is found on monocytes and AML blasts. We have created and characterized antibody-drug conjugates (ADCs) based on a humanized CLEC12A specific antibody to determine whether CLEC12A may be exploited as a therapeutic target for AML. The payload is a proprietary PBD prodrug with a beta-glucuronide trigger, and the linker-payload was conjugated through farnesyltransferase-mediated functionalization. The ADC demonstrated sub-nM cytotoxicity in vitro against several CLEC12A-positive cell lines including HL-60 and PL21. Leu234Ala/Leu235Ala (LALA) mutations were employed to reduce Fc gamma receptor binding and to avoid on-target toxicity. The LALA mutation-bearing ADC displayed a nearly 50-fold decrease in cytotoxicity towards CD34+ hematopoietic stem cells. Its potency was reduced but still sufficient with IC50 values of 61 pM and 15 pM against HL60 and PL21, respectively. Regardless of LALA mutation, the ADCs demonstrated potent antitumor activities with a complete regression at a dose of 0.5 mpk against a subcutaneous HL-60 SCID mouse xenograft model. When the LALA-mutated ADC was tested against a disseminated NSGA mouse model of HL-60-luc, all treated animals survived without clinical symptoms for three weeks after treatment, whereas vehicle-treated animals exhibited morbidity 19 days after treatment or 35 days after tumor implantation. The bone marrow of ADC-treated animals appeared to have nearly fully recovered, whereas that of vehicle-treated animals showed necrosis or tumor growth. In cynomolgus monkeys, the LALA-mutated ADC had a half-life of 82 hours at a dose of 0.2 mpk, and target-mediated drug disposition appeared weak or negligible. Our preclinical studies have shown that CLEC12A targeting ADC can be used as a therapeutics for treating AML. Citation Format: Jinwon Jung, Juhee Kim, Bora Lee, Jung A Kwon, Suyoun Lee, Byeongmin Yoo, Minji Ko, Ilhwan Ryu, Donghoon Yeom, Kyoungjae Lee, Jaehyun Eom, Hanbyul Lee, Jinhyung Ahn, Eunsil Sung, Weonkyoo You, Sang Hoon Lee, Myeong Joo Kim, Keon Woo Kwon, Hyun Joo Bae, Yun-Hee Park, Ho Young Song, Chul-Woong Chung. Preclinical study of a novel anti-CLEC12A antibody-drug conjugate with a glucuronide-protected pyrrolobenzodiazepine payload [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6296.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6296
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
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  • 2
    Online Resource
    Online Resource
    Abstract 1755: IKS03, a CD19-targeted antibody drug conjugate with enhanced efficacy and tolerability for treatment of B-cell lymphomas
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1755-1755
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1755-1755
    Abstract: Background: Lymphoma is the most common hematological malignancy with non-Hodgkin B-cell lymphomas (NHL), including those with high unmet clinical need such as relapsed/refractory Diffuse Large B Cell Lymphoma (DLBCL), and Mantle-Cell Lymphoma (MCL), representing 90% of all lymphoma cases. CD19 is an attractive target for antibody-directed lymphoma therapies as it is expressed in most B cell malignancies, with normal tissue expression limited to B-cells thus reducing any on-target toxicity concerns. Antibody Drug Conjugates (ADCs) are the focus of intense interest as a means to provide selective tumor killing with increased efficacy and less toxicity than standard of care chemotherapies. IKS03 is an ADC comprised of an anti-CD19 antibody conjugated to a proprietary DNA-crosslinking PBD prodrug and includes a tumor-selective glucuronide-trigger technology for payload release and activation. ADC activity requires processing by beta-glucuronidase, a lysosomal enzyme often upregulated in tumor cells, while normal tissues with low levels of the enzyme are less able to process the ADC and are differentially spared. Methods: IKS03 was generated via chemo-enzymatic bioconjugation at defined sites on the antibody yielding an ADC with a drug to antibody ratio of 2. In vivo efficacy was evaluated in CD19-expressing cell line-derived xenograft models in mice including Farage (DLBCL, Germinal Centre B-cell subtype), OCI-LY10 (DLBCL, Activated B-Cell subtype), Granta-519 (MCL) and Ramos (Burkitt’s lymphoma). Activity was compared to benchmark ADCs known to have demonstrated clinical efficacy. Efficacy was also assessed in low passage DLBCL patient-derived xenograft models of known genomic profile. Toxicology studies were conducted in cynomolgus monkeys with immunophenotyping by flow cytometry included to quantify the level of normal B-cells following IKS03 administration. Results: IKS03 is highly effective in causing tumor regressions in DLBCL models at doses that are well tolerated. Complete regressions were observed with a single dose of 0.1 mg/kg in the Farage xenograft model. IKS03 is also highly active in the Granta-519 MCL model, with complete regressions observed with a single dose of 0.1 mg/kg. Tumor regression was observed in a high-grade triple-hit lymphoma PDX model with a single 0.3 mg/kg dose. IKS03 was tolerated in monkeys at the highest dose tested of 1.5 mg/kg (single dose). IKS03 cross reacts with monkey CD19 and reduced B-cell depletion was observed in relation to comparator agents, even at doses much greater (1.5 mg/kg) than that needed for complete responses in B-cell lymphoma mouse models (0.1 mg/kg). Conclusion: Preclinical data demonstrates that IKS03’s advanced ADC design results in an increased therapeutic margin compared to traditional ADCs with DNA-crosslinking payloads, with increased efficacy and decreased toxicity. Citation Format: Jenny Thirlway, Adam Lodge, Daniel J. Williamson, Justyna Mysliwy, Jutta Deckert, Xavier Chauchet, Laura Cons, Yun-Hee Park, Hyun-Min Ryu, Na Ra Han, Ho Young Song, Chul-Woong Chung, Robert J. Lutz. IKS03, a CD19-targeted antibody drug conjugate with enhanced efficacy and tolerability for treatment of B-cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1755.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
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  • 3
    Online Resource
    Online Resource
    Abstract 1753: IKS014, a HER2-targeting antibody drug conjugate incorporating novel bioconjugation and tumor-selective linker technology with improved in vivo efficacy and tolerability
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1753-1753
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1753-1753
    Abstract: HER2 has long been a target of high interest for antibody and antibody drug conjugate (ADC) therapeutics due to its well-documented overexpression in breast, gastric and lung cancer. While trastuzumab and ado-trastuzumab emtansine (T-DM1) have become an integral part of treatment paradigms for HER2-positive cancer, the more recent approvals of the fam-trastuzumab deruxtecan (DS-8201) ADC and the Fc-engineered margetuximab antibody have highlighted the potential for continued improvement over existing HER2-targeting therapies. IKS014 is a HER2-directed ADC that incorporates site-directed conjugation and tumor-selective glucuronide-trigger linker technology to reduce systemic off-target toxicity while maximizing efficient intracellular lysosomal payload release, thus holding the promise of a wider therapeutic index. IKS014 was generated by site-specific conjugation via a proprietary beta-glucuronide linker to the microtubule agent MMAF with a drug-to-antibody ratio (DAR) 2. In vitro and in vivo activity was evaluated in HER2-positive preclinical models with varying HER2 expression levels in comparison to benchmark ADCs. Pharmacokinetics (PK) and tolerability studies were conducted in rodent and cynomolgus monkey. IKS014 conjugation resulted in a homogeneous ADC with defined DAR and good physio-chemical properties. In vitro, IKS014 demonstrated dose dependent specific cytotoxicity against Her2-positive cell lines. In JIMT-1 breast cancer xenografts with moderate HER2-expression (HER2 IHC 2+), IKS014 causes complete regressions at a single dose of 5 mg/kg and partial regressions at 1 mg/kg, while T-DM1 results in only tumor growth inhibition even at 15 mg/kg. Anti-tumor efficacy of IKS014 in NCI-N87 (HER2 3+) gastric xenografts is comparable to DS-8201 but superior to T-DM1 at equivalent single doses ranging from 1 to 5 mg/kg. In a HER2-positive patient-derived gastric cancer model (HER2 2+), IKS014 was highly active at 5mg/kg Q2W x2, while T-DM1 was inactive at the same dosing schedule. IKS014 demonstrated stable PK with a terminal half-life of 8.7 days in rat and 4.6 days in monkey, and DAR 2 was maintained for up to 4 weeks. In cynomolgus monkeys, IKS014 was tolerated at 12 mg/kg single dose and 5 mg/kg repeat dose without ocular or lung toxicity findings. IKS014 was highly efficacious against HER2-positive tumor xenografts in vivo, including models with moderate target expression, and compared favorably to clinically validated benchmark ADCs. This improved preclinical efficacy combined with stable PK and good tolerability profile warrants further development of this novel ADC for HER2-positive cancers. Citation Format: Jutta Deckert, Jenny Thirlway, Yun-Hee Park, Ho Young Song, Chul-Woong Chung, Xuesong Wang, Zhenshan Zhang, Robert J. Lutz. IKS014, a HER2-targeting antibody drug conjugate incorporating novel bioconjugation and tumor-selective linker technology with improved in vivo efficacy and tolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1753.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1753
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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