A first patient has been enrolled in the Phase I clinical trial of AK138D1 for the treatment of advanced malignancies in Australia. AK138D1 is being developed by Akeso. It is the company’s first antibody-drug conjugate (ADC) to enter clinical studies.
AK138D1 is a Human Epidermal Growth Factor Receptor 3 (HER3-)* targeting ADC, with a fully humanized immunoglobulin G1 monoclonal antibody anti-HER3 IgG1 antibody, patritumab. The investigational drug further includes the potent topoisomerase I inhibitor payload deruxtecan (DXd; an exatecan derivative) which is conjugated through a cleavable linker, MC-AAA (maleimide-alanine-alanine-alanine).
After binding to HER3 on tumor cells, the ADC is internalized into the tumor cells, where the linker is cleaved, releasing the membrane-permeable DXd. This leads to DNA damage and subsequent cell apoptosis.
Currently, Akeso has initiated patient enrollment for a Phase I dose-escalation and expansion clinical study in . This study will investigate the safety, tolerability, pharmacokinetics, and preliminary efficacy of AK138D1 for the treatment of advanced malignancies.
HER3, an emerging target
HER3 has emerged as an active target in cancer drug development and is the focus of ongoing research. Although experimental drugs targeting HER3 have, over the past 30 years, not shown satisfactory anti-tumor effects, studies indicate that HER3 is expressed or over-expressed in various malignancies, including breast cancer, ovarian cancer, lung cancer, colorectal cancer, melanoma, head and neck cancers, cervical cancer, and prostate cancer.
Additionally, up-regulation of HER3 and its synergistic interactions with other receptors contribute to tumor initiation, metastasis, and resistance to certain anticancer treatments, such as resistance to EGFR-targeted therapies, endocrine therapy in breast cancer, HER2-targeted therapies, and chemotherapy. [1]
Targeted HER3 therapies, which involving inhibition of HER3 kinase activity, blocking heterodimerization, and using antibodies, including (but not limited to) patritumab are being developed to treat advanced or metastatic breast cancer.[1]
With the observed limited effectiveness of single treatments, the targeted distribution of a cytotoxic payload, which has been achieved by ADCs, causes an anti-tumor response, and cell damage, shows promise as a treatment for late-stage breast cancer. [1]
IO 2.0 + ADC-strategy
A key element of the Akeso’s mission is the IO 2.0 + ADC strategy. Akeso’s self-developed, first-in-class bispecific antibodies, cadonilimab (PD-1/CTLA-4) and ivonescimab (PD-1/VEGF), have both received regulatory approval and are now available to patients in China.
The continued development of differentiated ADC therapies, including AK138D1, further extend the company’s ability to explore the full clinical potential of its innovative in-house pipeline and to create synergistic new combination treatment options includes that multiple checkpoints and tumor targets.
Pivotal moment
“The initiation of the clinical study for AK138D1 in Australia marks a pivotal moment in Akeso’s strategic advancement into next-generation ADC therapies,” said Xia Yu, Founder, Chairwoman, President and Chief Executive Officer of Akeso.
“Building on our global prominence in bispecific antibodies and a robust pipeline of high-potential drug candidates, the development of AK138D1 and subsequent ADCs/bispecific ADCs will significantly bolster our product offering. This is part of Akeso’s continued effort to redefine standard of care in cancer treatment,” Yu added.
“Following our achievements in bispecific antibody development, ADC therapies have emerged as a strategic priority for Akeso. Based on our extensive experience in bispecific antibody development, we are excited by the potential of our proprietary ADCs and bispecific ADCs. Our goal is to enhance drug efficacy while minimizing ADC toxicity, offering transformative treatment alternatives for patients worldwide. Moreover, Akeso has established cutting-edge ADC research, pilot production, and manufacturing facilities. These investments position us for high-quality clinical development and for global market expansion of our ADC portfolio,” he concluded.
Note:* Human Epidermal Growth Factor Receptor 3 (HER3) is a transmembrane protein that plays a crucial role in cell growth, survival, and differentiation,
Clinical trials
A Phase I Study of AK138D1 in the Treatment of Advanced Solid Tumors – ClinicalTrials.gov ID NCT06730386
Reference
[1] Zhu M, Yu M, Meng Y, Yang J, Wang X, Li L, Liang Y, Kong F. HER3 receptor and its role in the therapeutic management of metastatic breast cancer. J Transl Med. 2024 Jul 17;22(1):665. doi: 10.1186/s12967-024-05445-8. PMID: 39020378; PMCID: PMC11253420.
Featured image licensed under the Unsplash+ License. Used with permission
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