Biosion submitted the IND application for BSI-992, a TROP2 ADC, on April 9th, 2024 in China. The TROP2 targeting antibody, discovered by Biosion, was licensed to OBI Pharma in 2021.
| OBI ADC Technology |
BSI-992/OBI-992
OBI-992 is a TROP2-directed antibody-drug-conjugate (ADC) that carries a potent topoisomerase I inhibitor and uses a hydrophilic, enzyme-cleavable linker. Upon binding to TROP2 on the surface of cancer cells, OBI-992 is internalized into the cell and trafficked to lysosomes where the linker is cleaved by cathepsin B, releasing the payload exatecan to kill the cancer cells.
In April 2024, OBI presented the results of preclinical studies of OBI-992 at the AACR Annual Meeting.
In various CDX and PDX models, a single dose of OBI-992 at 3 or 10 mg/kg exhibited remarkable tumor growth inhibition. Notably, the antitumor efficacy of OBI-992 surpassed that of datopotamab deruxtecan (Dato-DXd) across different CDX and PDX models. OBI-992 demonstrated a bystander killing effect as OBI-992 was able to kill TROP2-negative xenografts in the presence of nearby TROP2-positive cells. OBI-992 showed superior efficacy to Dato-DXd in the CDX model overexpressing Pgp or BCRP. These findings suggest that OBI-992 was not affected by the Pgp- and BCRP-mediated multidrug resistance. In the HRD CDX model at suboptimal doses, combination of OBI-992 with olaparib or talazoparib displayed remarkable synergistic effects.
Ex vivo serum stability demonstrated that OBI-992 exhibited better linker stability than the benchmark datopotamab deruxtecan (Dato-DXd). In vivo PK evaluation in rats showed that OBI-992 had lower Cmax and AUC of free payload than Dato-DXd, indicating a better PK profile of OBI-992 in rats...... Major toxicities in monkeys were target-related skin lesions. The highest non-severely toxic dose (HNSTD) was determined to be 60 mg/kg.
The TROP2 antibody (R4702) displayed different binding epitopes from sacituzumab and datopotamab...... The payload exatecan demonstrated excellent ICD effects. Relatively higher cytotoxicity was observed by exatecan when compared to that of Dxd and SN-38...... A mutation R364H was identified in TOP1 in the resistance study with OBI-992, which is critical for the binding to TOP1 inhibitors camptothecin analogs.
Anti-TROP2 ADC
More than a dozen ADC products targeting TROP2 are currently under development. A large number of them in the early stage are discovered by Chinese companies.
|
Product |
Company |
Stage |
Indication |
Initiation |
|
Sacituzumab Govitecan |
Gilead |
Marketed |
Approval: BC/UC Trial: OC/PC/CRC | 2020.04 |
|
Datopotamab Deruxtecan |
Daiichi Sankyo/AstraZeneca |
BLA |
BLA: BC/NSCLC Trial: Pan tumors |
2024.02 |
|
Sacituzumab Tirumotecan |
Kelun/Merck |
BLA |
BLA: TNBC Trial: NSCLC |
2023.12 |
|
ESG-401 |
Escugen/Levena |
Ph1/2 |
Cancer |
2021.09 |
|
FDA018 |
SPH/Fudan-Zhangjiang |
Ph1 |
Cancer |
2021.11 |
|
SHR-A1921 |
Ph2/3 |
Cancer |
2022.02 |
|
|
BIO-106 |
BiOneCure |
Ph1/2 |
Cancer |
2022.04 |
|
BL-M02D1 |
Ph1/2 |
Cancer |
2022.05 |
|
|
DB-1305/BNT323 |
DualityBio/BioNTech |
Ph1/2 |
Cancer |
2022.09 |
|
BAT8008 |
Ph1/2 |
Cancer |
2022.11 |
|
|
MT-302 |
Myeloid |
Ph1/2 |
Epithelial cancer |
2023.08 |
|
9MW2921 |
Ph1/2 |
Cancer |
2023.08 |
|
|
LCB84 |
LegoChem |
Ph1/2 |
Cancer |
2023.10 |
|
HS-20105 |
Hansoh |
Ph1 |
Cancer |
2023.11 |
|
IBI130 |
Ph1/2 |
Cancer |
2024.03 |
|
|
OBI-992/BSI-992 |
OBI/Biosion |
IND |
Cancer |
2024.01 |
|
GQ1010 |
GeneQuantum/Pyramid |
IND |
Cancer |
2024.02 |
|
JS108 |
Junshi/Dac |
Terminated in Ph1 |
Cancer |
2020.10 |
Orange: China-based company
Sacituzumab Tirumotecan
Kelun-Biotech presented efficacy and safety data of SKB264 from a Phase II expansion study in TNBC at 2023 SABCS. Among the 59 treated patients with locally advanced or metastatic TNBC, the objective response rate (ORR) was 42.4%, with 3 patients achieving complete response (CR); the disease control rate (DCR) was 76.3%; the median duration of response (mDoR) was 11.5 months. In addition, median progression-free survival (mPFS) was 5.7 months, and the median overall survival (mOS) reached 16.8 months, with 12-month and 24-month OS rates of 65% and 39.5%, respectively. Nearly 40% of patients in the study treated with SKB264 were alive at two years.. In the subgroup of patients with high TROP2 expression (H-score>200, n=32), the ORR was 53.1%, mDoR was 11.1 months, mPFS was 5.8 months, mOS had not been reached, and the 12-month and 24-month OS rates were 65.3% and 57.3% respectively.
ESG-401
Escugen Biotech reported the preliminary results from a first-in-human study of ESG40 at the ASCO Annual Meeting. As of Feb 3, 2023, 35 pts with a median age of 53 were treated with ≥1 dose of ESG401 during escalation at doses of 2-20 mg/kg once Q3W (Regimen A), or 12-16 mg/kg D1,8,15 in a 4-week cycle (Regimen B). 80% of pts were ECOG = 1, 63% of pts were 3L+; median 4 (2-10) prior lines, 94% of pts had visceral metas (11% brain, 63% liver, 60% lung) at baseline. Only one patient treated with 20 mg/kg experienced DLT. The MTD has not reached either regimen. The most common TRAEs were leukopenia (80%), neutropenia (69%), anemia (66%), fatigue (54%), nausea (51%), and vomiting (46%). The most common ≥ Grade 3 TRAEs were leukopenia (29%) and neutropenia (31%). There was no ≥ Grade 3 thrombocytopenia, diarrhea, skin rash, or oral mucositis. No Interstitial Lung Disease (ILD) was observed. Of 33 efficacy evaluable (EE) pts, 12 partial responses (PR) were observed and 4 pts had achieved SD ≥24 wks. The first dose level found PR (16 mg/kg Q3W) and afterward were taken as therapeutically relevant doses (TRD). The ORR and DCR were 36% (4/11) and 64% (7/11) in 11 TRD pts with TNBC, while 62% (8/13) and 77% (10/13) in 13 TRD pts with HR+/HER2-BC. Two pts with brain metas both got an obvious intracranial response (one pt whose intracranial lesion was significantly reduced to too small to measure). Until the cut-off date, 11 (31%) pts remained on treatment. Three pts were treated over 12 mons and the longest on-treatment duration was 12.9 mons. One pt had consistent PR up to 10.8 mons.
SHR-A1921
Hengrui delivered the results of the phase 1 study of SHR-A1921 at the AACR Annual Meeting. As of Oct 21. 2022, 38 enrolled patients were included for analysis: 18 enrolled during dose-escalation (1.5 mg/kg, n=1; 3.0 mg/kg, n=4; 4.0 mg/kg, n=8; 6.0 mg/kg, n=5) and 20 during dose-expansion (3.0 mg/kg). 71.1% (27/38) were driver gene-negative non-small cell lung cancer (NSCLC) patients who had previously received platinum-based chemotherapy and anti-PD-(L)1 antibody. 4 patients reported dose-limiting toxicities, with all being grade 3 stomatitis (6.0 mg/kg, n=3; 4.0 mg/kg, n=1). The MTD was established as 4.0 mg/kg. Across all dose cohorts, the most common treatment-related adverse events (TRAEs; ≥30%) were nausea (71.1%), stomatitis (65.8%), anemia (42.1%), vomiting, decreased appetite, decreased weight, and rash (36.8% each). Grade ≥3 TRAEs occurred in 12 patients (31.6%); of these, the most common was stomatitis (n=7, 18.4%), and all other events were reported in ≤2 patients. No patients discontinued study treatment due to TRAEs. As of cut-off date, 10 patients (NSCLC, n=5; triple-negative breast cancer, n=2; ampullary cancer, n=2; ovarian cancer, n=1) had partial response: 4 confirmed and 6 requiring further confirmation. The objective response rate was 33.3% (10/30; 95% CI 17.3-52.8) and disease control rate was 80.0% (24/30; 95% CI 61.4-92.3) in evaluable patients.
BL-M02D1
SystImmune presented the preclinical evaluation of BL-M02D1 at the AACR Annual Meeting. BL-M02D1 achieves a high drug-to-antibody-ratio (DAR=8) with a highly stable linker. It is comprised of a novel monoclonal antibody against Trop2 (hu4D3), a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04). The antitumor efficacy of BL-M02D1 was evaluated in comparison to a commercialized Trop2-targeting ADC, IMMU-132, in xenograft tumor models. BL-M02D1 exhibited stronger tumor inhibition capacity than IMMU-132 at lower doses in the gastric cancer cell line NCI-N87, the breast cancer cell line MDA-MB-231, and the non-small cell lung cancer cell line HCC827 xenograft models. BL-M02D1 exhibited potent bystander effects, exemplified by strong tumor inhibition in a heterogeneous xenograft model of Trop2-positive and Trop2-negative tumor cells (A431 and SW620). This characteristic of BL-M02D1 was also compared to IMMU-132. In the heterogeneous Trop2 xenograft model (A431 and SW620), BL-M02D1 exhibited higher tumor inhibition capacity than IMMU-132, indicating that BL-M02D1 possess a more potent bystander effect than IMMU-132.
DB-1305
Duality Biologics reported the preliminary clinical results from the phase (Ph) I/IIa study of DB-1305. As of 07 Apr 2023, 44 pts (2 mg/kg, n=1; 4 mg/kg, n=20; 5 mg/kg, n=17; 6 mg/kg, n=6) were enrolled in the Ph1. The median treatment duration was 1.5 (range, 0.7-6.1) months with 25 pts (56.8%) remaining on treatment. Pts had 3 median prior lines of therapy (range, 1-6). Three patients dosed at 6 mg/kg experienced dose-limiting toxicities (i.e., stomatitis, febrile neutropenia, and white blood cell decreased), and the maximum tolerated dose was established as 5 mg/kg. The most common (≥30%) treatment-related adverse event (TRAE) was stomatitis (75.0%). The most common (≥10%) Gr≥3 TRAE was stomatitis (22.7%), while all other events were reported in ≤2 pts. No TRAE led to death. The initial PK results suggest that exposure of DB-1305 increased with dose. The half-life of DB-1305 is approximately 3-4.5 days at the dose range of 4-6 mg/kg. The average systemic ADC/payload molar ratio is approximately 80, indicating ADC stability in systemic circulation. As of cut-off date, 7 pts (non-small cell lung cancer [NSCLC], n=6; fallopian tube cancer, n=1) had partial responses, 4 confirmed, and 3 requiring further confirmation. The objective response rate (ORR) was 30.4% (7/23), and disease control rate (DCR) was 87.0% (20/23). Thirteen NSCLC pts had an ORR of 46.2% (6/13), with a DCR of 92.3% (12/13).
BAT8008
Bio-Thera presented the preclinical data at the SABCS. BAT8008 consists of an enzymatically cleavable linker and a topoisomerase I inhibitor as the payload, with DAR of 6. BAT8008 demonstrated potent in vitro cell growth inhibitory activity to Trop2-positive cells with IC50 values of < 1 nM. In an in vitro bystander killing assay, proliferation of Trop-2-negative cells was potently inhibited by addition/transfer of culture medium of BAT8008-treated Trop-2-positive cells, but not that of BAT8008-treated Trop-2-negative cells, indicating the bystander killing effect of the released payload in the culture medium. Less than 0.1% of the payload was released from BAT8008 when incubated with human or monkey plasma for 7 days in 37°C, suggesting the stability of BAT8008 in blood circulation. Single dose of BAT8008 at 1 and 2.5 mg/kg could inhibit 73% and 81% tumor growth in the Trop-2-positive MDA-MB-468 and MX-1 xenograft mice model, respectively. BAT8008 also demonstrated superior tumor inhibition activity than a modified ADC using Daiichi’s ADC technology or Trodelvy in a pancreatic BxPC-3 xenograft mice model. In addition, BAT8008 showed favorable pharmacokinetic and safety profiles in cynomolgus monkeys with the highest non-severely toxic dose (HNSTD) of at least 25 mg/kg when dosed once every two weeks for 3 times. Together these results indicate that BAT8008 could potentially provide a therapeutic benefit to treat TROP2-positive breast cancers in clinical trial.
GQ1010
GeneQuantum reported the preclinical characterization of GQ1010. GQ1010 demonstrated more potent in vitro cytotoxicity than DS1062 in diverse Trop2+ cancer cell lines tested. GQ1010 also exhibited superior bystander killing than DS1062. GQ1010 further demonstrated strong in vivo antitumor activities in different CDX models including TNBC, gastric, head and neck (H&N) and pancreatic cancer, and the efficacies were better than DS1062 and Trodelvy®, consistent with the in vitro data. Ex vivo plasma stability data confirmed GQ1010 contains highly stable linker with a minimal DAR reduction and payload shedding, indicating expanded therapeutic window than the benchmark ADCs. Free payload distribution analysis in NCI-N87 model showed high target-specific payload delivery and ~90X payload enrichment in tumor than in plasma, confirming minimal shedding of the payload from GQ1010 during circulation in vivo. In the monkey toxicity study, GQ1010 demonstrated excellent safety without signal of interstitial lung disease (ILD) up to 80 mg/kg dosing.
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