IL3RA-Targeting Antibody–Drug Conjugate BAY-943 with a Kinesin Spindle Protein Inhibitor Payload Shows Efficacy in Preclinical Models of Hematologic Malignancies

IL3RA (CD123) is the alpha subunit of the interleukin 3 (IL-3) receptor, which regulates the proliferation, survival, and differentiation of hematopoietic cells. IL3RA is frequently expressed in acute myeloid leukemia (AML) and classical Hodgkin lymphoma (HL), presenting an opportunity to treat AML and HL with an IL3RA-directed antibody–drug conjugate (ADC). Here, we describe BAY-943 (IL3RA-ADC), a novel IL3RA-targeting ADC consisting of a humanized anti-IL3RA antibody conjugated to a potent proprietary kinesin spindle protein inhibitor (KSPi). In vitro, IL3RA-ADC showed potent and selective antiproliferative efficacy in a panel of IL3RA-expressing AML and HL cell lines. In vivo, IL3RA-ADC improved survival and reduced tumor burden in IL3RA-positive human AML cell line-derived (MOLM-13 and MV-4-11) as well as in patient-derived xenograft (PDX) models (AM7577 and AML11655) in mice. Furthermore, IL3RA-ADC induced complete tumor remission in 12 out of 13 mice in an IL3RA-positive HL cell line-derived xenograft model (HDLM-2). IL3RA-ADC was well-tolerated and showed no signs of thrombocytopenia, neutropenia, or liver toxicity in rats, or in cynomolgus monkeys when dosed up to 20 mg/kg. Overall, the preclinical results support the further development of BAY-943 as an innovative approach for the treatment of IL3RA-positive hematologic malignancies.

A Phase 1 Dose-Escalation Study of LH031, a Kinesin Spindle Protein Inhibitor, in Patients with Refractory/Resistance Multiple Myeloma

PURPOSE: Kinesin spindle protein is an attractive target for cancer treatment since it plays an important role in mitosis without directly affecting microtubules. LH031 is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity.. This phase 1 study was conducted to evaluated dose limiting toxicities (DLTs) and determined a maximum tolerated dose (MTD) for LH031 in Chinese patients with Refractory/Resistance Multiple Myeloma (RRMM).The pharmacokinetics (PK) and preliminary efficacy of LH031 were also evaluated. METHODS: A non-randomized, single-center, open-label, dose-escalation phase 1 trial was conducted to evaluate the safety, tolerability, pharmacokinetics and efficacy of single or multiple escalation dose (20 mg, 30 mg, 40 mg, 50 mg) of LH031 given as schedule of oral once a day. LH031 was administered on Day 1~5 of each week for 3 weeks (21 days) per cycle. A standard 3+3 dose escalation design was employed. An expansion cohort was conducted at the MTD. Pharmacokinetics was evaluated in plasma. A major efficacy evaluation was performed at the end of each treatment cycle. RESULTS: The study is still on going, at present there are 6 patients received LH031 and completion of all visits, divided equally into 20mg and 30mg cohort. Patients in each cohort had received a median of 6 prior therapies. DLTs reported in two patients dosed at 30mg. Both of the DLTs were neutropenia. The most commonly reported treatment-related AEs were hematological toxicity (e.g. neutropenia, lymphocytopenia, leukocytopenia) that were similar to other Eg5 inhibitors. The main severe adverse events (CTCAE grade 3 or 4) in the 20mg and 30 mg dose groups were leukocytopenia and neutropenia, and they were all reversible. Neurotoxicity related to LH031 was not observed. Efficacy data demonstrated that the best response was Stable Disease(SD) and Disease Control Rate (DCR, ≥SD[≥8 weeks]) was 50%. The longest treatment time was 177 days, even though PFS was determined according to the last tumor evaluation before the COVID period (D88). The PK data shows that T1/2 are approximately 20h in Chinese patients, which is longer than Caucasian (10h); Chinese AUC for 20mg is also higher than that of Caucasian (1996 h*ng/ml vs. 476 h*ng/ml) ; the exposure at 20mg dose group is close to that at 50 mg dose in Caucasian. These PK parameter indicates that the elimination of LH031 is slower in Chinese patients compared with Caucasian. CONCLUSIONS: The current phase 1 study showed that LH031 was an accepted safety profile at 20mg. DLTs was expected and reversible. MTD is to be determined by recruiting 3 more subjects at 20mg dose. It demonstrated that the elimination rate of LH031 in Chinese patients was slower than Caucasian. The monotherapy showed some benefit to RRMM, Phase 2 clinical trials are being planned to include various combination therapies with existing treatments (e.g. lenalidomide, dexamethasone, bortezomib) for MM to benefit more potential refractory/resistance MM patients. Disclosures Song: Link Health Group: Current Employment.

Synthesis, Docking Studies and Biological Evaluation of Novel N-(2-(3-fluorophenyl)- quinolin-5-yl)benzamide Derivatives as Potent Anti-breast Cancer Agents

A novel series of quinoline benzamide derivatives have been synthesized and screened for their anticancer activity against a breast cancer cell line (MDA-MB-231) by MTT assay method. All the synthesized compounds were confirmed by spectral characterization viz. FTIR, 1H & 13C NMR and MS. All the molecules demonstrated potency less than 35 μM and were better than standard cisplatin but not comparable to doxorubicin. Compound 3i (IC50 = 6.86 μM) exhibited better promising anti-breast cancer activity among various synthesized molecules and in addition, docking of compound 3i into kinesin spindle protein (KSP) active site was performed in order to predict the affinity and the orientation at the enzyme active site.

Antibody-drug Conjugates with Novel Kinesin Spindle Protein Inhibitor Payloads and a Tailor-made Linker Chemistry

With the approval of meanwhile five ADCs and more than 80 ADCs in clinical trials, the ADC landscape has developed rapidly during the last decade. However, as indicated also by the large number of ADCs which failed in the clinic, it remains challenging to achieve a sufficiently large therapeutic window in cancer patients.