3D011 is a prodrug composed of ABT-869 (Linifanib), a multi-target anti-angiogenesis small molecule, and a specific pentapeptide, which are connected by a linker (dodecylic acid). 3D Medicines has submitted the Investigational New Drug (IND) application of 3D011, and the Phase 1 clinical trial in patients with advanced solid tumors is about to be initiated.
Multi-target Anti-angiogenesis Small Molecule Prodrug
Abnormal neovascularization, a hallmark of solid tumors, plays a key role in tumor progression. ABT-869 (Linifanib) is an oral multi-target drug, which significantly inhibits angiogenesis-related kinases including VEGFRs, PDGFRs, CSF1R, c-KIT and FLT1/3. Clinical trials of ABT-869 has demonstrated anti-tumor efficacy comparable to similar products, but also high systemic toxicity. To improve its pharmacokinetic characteristics and reduce its systemic toxicity, we have designed a prodrug - 3D011, which is formed by linking ABT-869 and a specific pentapeptide (Asp-Glu4) with a linker (dodecylic acid). 3D011 is stable in vitro, but the linker and the specific pentapeptide could be degraded in vivo by tissue-specific proteases and hydrolases, releasing the active molecule ABT-869 (Linifanib) at the tumor site. Preclinical studies have demonstrated that 3D011 has anti-tumor activity comparable to ABT-869 and less toxicity at the same dose. A series of pre-clinical studies of 3D011, including in vivo and in vitro pharmacokinetic studies, pharmacokinetic/toxicokinetics studies, and safety pharmacology studies have been completed to support clinical trials in patients with advanced tumors.
The IND of 3D011 has been approved by the NMPA, and Phase 1 clinical trials to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of monotherapy in patients with advanced malignant solid tumors are in planning. Also, the safety profile and efficacy of 3D011’s combination with KN035 (PD-L1 antibody) will be explored on the basis of Phase 1 results.