On November 4, 2019 Harbour BioMed (HBM) reported the start of the first clinical trial of its next-generation fully human anti-CTLA-4 antibody (HBM4003) for the treatment of patients with advanced solid tumors (Press release, Harbour BioMed, NOV 4, 2019, View Source [SID1234550228]). This trial is the first with a fully human antibody based on heavy chain only antibody technology (HCAb). HBM4003 has shown potential for increased anti-tumor activity based on enhanced antibody dependent cell toxicity (ADCC) mediated Treg depletion and a favorable safety profile resulting from reduced half-life.
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In preclinical studies, HBM4003 demonstrated potent anti-tumor activity with much lower systemic drug exposure, suggesting a potentially significant improvement in its therapeutic profile. HBM presented preclinical study results of HBM4003 in April 2019 at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper). The trial is design led to assess the safety, pharmacokinetic profile and preliminary anti-tumor activity of HBM4003 in patients with advanced solid tumors.
"HBM4003, based on our proprietary human HCAb platform, underscores the potential for heavy chain only antibodies in developing the next-generation of immuno-oncology therapeutics for patients," said Dr. Jingsong Wang, Founder, Chairman and CEO of Harbour BioMed. "This study, being conducted in Australia, is the first part of a global development program, with US and China clinical trials — including combination studies — expected to begin in the near future." Dr. Wang added, "HBM is rapidly building its pipeline, with HBM4003 advancing to the clinic in less than three years and with additional mono- and bi-specific antibodies against various targets in pre-clinical development."
CTLA-4 is one of the major negative regulators of T-cell responses. Anti-CTLA-4 antibodies are immune checkpoint inhibitors with proven value in cancer immunotherapy by increasing T-cell activity to attack tumor cells. Despite demonstrated efficacy, their safety profiles have been a barrier to broader application as both mono- and combination therapies. Preclinical studies have shown that HBM4003’s immune stimulatory activity is driven by two mechanisms: depletion of immune suppressing Treg through enhanced ADCC and; inhibition of negative signaling from the interaction of CTLA-4 with the co-stimulatory molecule B7.
"Advanced solid tumors including melanoma remain a major challenge despite improvements in the standard of care," said Prof. Paul de Souza, Dean of Medicine at the University of Wollongong Australia, and a principal investigator for this study. "Preclinical studies of HBM4003 have shown great potential. This trial provides the first opportunity to evaluate how this promising compound will perform in the treatment of solid tumors."
About Heavy Chain Only Antibodies (HCAb)
Heavy-chain only antibodies consist only of two heavy chains; they lack the two light chains usually found in traditional antibodies. HCAb’s are smaller than conventional antibodies, potentially allowing for increased tissue penetration. These antibodies also maintain IgG-like pharmacokinetic properties and immune activation (Fc) functions. HCAbs can bind antigens despite having only VH domains and have shown similar specificity to regular antibodies.
HBM’s HCAbs, which are generated by its fully human transgenic mouse platform, further enable the design of versatile formats of antibodies capable of addressing different mechanisms of action and use in different applications. HCAbs are naturally generated human antibodies against desired targets; thus there is no need for humanization to reduce immunogenicity.