Advances in TROP-2 Directed ADCs.pdf

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Advances in TROP-2 Directed ADCs
In recent years, there has been explosive growth in the development of antibody-drug
conjugates (ADCs). Similar to HER2, Trop-2 is a new hot target for research. Trodelvy has
been one of the products receiving much attention in recent years, and Dato-DXd from
AstraZeneca/Daiichi Sankyo is also advancing rapidly.
First Phase III results for Dato-DXd
On July 3, 2023, AstraZeneca/Daiichi Sankyo announced the latest results of the Phase
III clinical interim analysis of the new Trop2 ADC drug Dato-DXd for non-small cell lung
cancer (NSCLC). TROPION-Lung01 set dual primary endpoints, progression-free survival
(PFS) and overall survival (OS). The result shows that Dato-DXd demonstrated a
statistically significant improvement for the dual primary endpoint of PFS
compared to docetaxel.
However, for the dual primary endpoint of OS, the data were not mature and an early
trend was observed in favor of Dato-DXd versus docetaxel that did not meet the
prespecified threshold for statistical significance at this interim analysis. In the trial,
Dato-DXd's safety profile was consistent with previous clinical trials with no new safety
signals identified.
Datopotamab deruxtecan (Dato-DXd, DS-1062) is an investigational TROP2-directed
ADC designed using Daiichi Sankyo's proprietary DXd ADC technology. Dato-DXd
consists of a humanized anti-TROP2 IgG1 monoclonal antibody conjugates with a number
of topoisomerase I inhibitor payloads, exatecan derivative (DX-8951 derivative, DXd), via
a tetrapeptide-based cleavable linker. It can target the delivery of cytotoxic agents into
cancer cells, reducing systemic exposure to cytotoxic agents compared to usual
chemotherapy.

Figure 1. Structure of Dato-DXd, source: Daiichi Sankyo
TROPION-Lung01 is a randomized, open-label, global, multicenter phase III clinical
designed to evaluate the efficacy and safety of Dato-DXd (6.0 mg/kg) versus docetaxel
(75 mg/m2) in patients with locally advanced or metastatic NSCLC who have received at
least one prior treatment. The primary endpoints of the study were OS and PFS as
assessed by the blinded independent central review (BICR). Key secondary endpoints
include investigator-assessed PFS, objective response rate (ORR), duration of response,
time to response, and disease control rate as assessed by the BICR and investigators,
and safety.
In addition, Dato-DXd is also being explored in the field of NSCLC in combination with
immune checkpoint inhibitors. The latest results from the Phase Ib clinical
TROPION-Lung02 study, presented at ASCO 2023, further demonstrate the significant
efficacy and favorable safety profile of Dato-DXd in combination with pembrolizumab with
or without platinum-based chemotherapy in patients with primary or treated advanced
NSCLC without actionable genomic alterations (AGAs).
The results showed that in the treatment-naï
ve cohort, the ORR was 50% in the doublet
cohort, with 15 cases of confirmed partial response (PR) and 2 cases of unconfirmed PR;
the ORR was 57% in the triplet cohort, with 1 case of confirmed complete response (CR)
and 29 cases of confirmed PR. In addition, the DCR was 91% in both the doublet and
triplet cohorts, and the median DoR was not yet reached in either group.
Across previously untreated and pretreated patients, the ORR was 38% in the doublet
cohort and 49% in the triplet cohort. DCR was 84% and 87% in the two groups; median
PFS was 8.3 months and 7.8 months, respectively, but data are not yet mature.

Figure 2. TROPION-Lung02 study, Source: AstraZeneca company presentation.
Dato-DXd is currently in a worldwide clinical development program for the TROPION
series, designed to evaluate its efficacy and safety in a variety of solid tumors including
NSCLC, triple-negative breast cancer, and HR-positive/HER2 low-expressing or negative
breast cancer. In addition, the product has multiple clinical under evaluation in new
combinations.

Figure 3. TROPION series study, Source: Daiichi Sankyo official website.
TROP2-Directed ADCs Under Investigation
Besides Dato-DXd, there are many other TROP-2 ADCs under investigation. Here we
describe in detail the TROP2 ADCs in clinical trials.
Drug Phase Company Indications
Trodelvy Approved
Gilead
Seagen
BSP Pharmaceuticals
TNBC;
urothelial carcinoma;
HR+/HER2- BC
Dato-DXd III
AstraZeneca
Daiichi Sankyo
TNBC; BC; NSCLC; Solid
tumors; gastric cancer;
urothelial carcinoma
SKB-264 III
Kelun Biotech
Merck
Klus Pharma
TNBC; BC; NSCLC;
bladder cancer; ovarian
epithelial carcinoma
BIO-106 I/II BiOneCure Therapeutics Solid tumors
DB-1305 I/II DualityBio Solid tumors
ESG-401 I/II
Escugen
Levena Biopharma
Solid tumors
BAT-8008 I Bio-Thera Solid tumors
BL-M02D1 I
Baili Pharm
Systimmune Inc
Solid tumors;TNBC; BC;
NSCLC
DAC-002
JS108
I
DAC BIOTECHNOLOGY
Junshi Bio
Solid tumors;TNBC; NSCLC
FDA018 I Shanghai Fudan-Zhangjiang Solid tumors

Bio-Pharmaceutical
SHR-A1921 I Hengrui Medicine Solid tumors
Table. Trop-2 ADC pipelines
Trodelvy (Sacituzumab govitecan)
Trodelvy, a novel ADC targeting Trop-2, is comprised of a humanized monoclonal
antibody hRS7IgG1κ (sacituzumab) conjugated with SN-38, the active metabolite of
irinotecan, via a hydrolysable linker (CL2A) with a drug-to-antibody ratio (DAR) of 7.6:1.
Figure 4. Structure of Sacituzumab govitecan, source: Gilead Sciences, Inc.
Sacituzumab govitecan was originally developed by Immunomedics, and in September
2020, Gilead acquired Immunomedics for $21 billion.
 ▶ On April 22, 2020, the FDA approved Trodelvy for treating adult patients with metastatic
triple-negative breast cancer (TNBC) who have received at least two prior therapies for
metastatic disease, making it the first FDA-approved anti-Trop-2 ADC.

 ▶ In April 2021, Trodelvy received FDA approval for the second-line treatment of
triple-negative breast cancer (TNBC) and accelerated approval for the second-line
treatment of advanced urothelial carcinoma (UC).
 ▶ On February 3, 2023. FDA has approved Trodelvy for treating adult patients with
unresectable locally advanced or metastatic HR+/HER2- breast cancer who have
received endocrine-based therapy and at least two additional systemic therapies in the
metastatic setting.
On March 5, 2023, OncLive published real-world results of Trodelvy in patients with
metastatic triple-negative breast cancer (TNBC). This retrospective analysis examined
patients treated between January 1, 2021, and December 31, 2022, and showed that
Trodelvy produced significant and meaningful disease response and tolerability in a large
pretreated metastatic triple-negative breast cancer population.
Since its launch, Trodelvy has reported first full-year results of $380 million and a total
revenue of $680 million in 2022. According to US securities firm Cowen, the world's first
Trop-2 ADC drug, Trodelvy, is expected to reach a maximum annual sales revenue of
US$4 billion.
SKB-264
SKB264 is an innovative ADC targeting TROP2 developed by Kelun Biotech, consisting of
a humanized monoclonal antibody targeting TROP-2 and a novel topoisomerase I
inhibitor linked to an enzymatically cleavable linker. SKB264 has been granted
breakthrough therapy designation by the Center for Drug Evaluation (CDE) of the National
Medical Products Administration (NMPA) for the treatment of locally advanced or
metastatic triple-negative breast cancer and locally advanced or metastatic
EGFR-mutated non-small cell lung cancer.
Data from a Phase II expansion study in patients with treated locally advanced or
metastatic non-small cell lung cancer (NSCLC) were presented in a poster session at the
2023 ASCO Annual Meeting. SKB264 demonstrated promising efficacy and a
manageable safety profile.

This is a phase I/II multicenter dose-escalation/expansion study (NCT04152499) in
patients with relapsed or refractory locally advanced/metastatic NSCLC and other tumor
types. All NSCLC patients received SKB264 at a dose of 5 mg/kg IV Q2W. Data are as of
February 9, 2023, with a median follow-up of 11.5 months.
Among the 39 patients with evaluable responses, the ORR was 44% (17/39), the median
DoR was 9.3 months, and the 6-month DoR rate was 77%. For the EGFR wild-type
subgroup (prior median 2nd-line therapy, including anti-PD-1/L1), the ORR was 26%
(5/19), DCR was 89% (17/19), median PFS was 5.3 months, and 9-month OS rate was
80.4%. For the TKI-resistant EGFR mutant NSCLC subgroup (50% also received at least
one chemotherapy failure), the ORR was 60% (12/20), DCR was 100% (20/20), median
PFS was 11.1 months, and the 9-month PFS rate was 66.7%.
BIO-106
BiOneCure Therapeutics developed BIO-106 with its proprietary TAMTM payload
technology to achieve uniformly high drug loading, giving BIO-106 an improved
therapeutic window and safety profile. BiOneCure owns all international proprietary
intellectual property rights for BIO-106 including the Trop-2 antibody and payload.
In April 2022, the FDA cleared the IND for BIO-106, known as StarBridge-1, a Phase I/II,
multicenter, open-label study to evaluate the safety, pharmacokinetics and preliminary
anti-tumor activity of BIO-106 as monotherapy and in combination with pembrolizumab in
patients with advanced cancers.
DB-1305
DB-1305 was developed by DualityBio and entered clinical phase I/II studies in June 2022
(NCT05438329).
DB-1305 is a targeted ADC that couples an anti-Trop-2 antibody with a novel
topoisomerase I inhibitor, P1021, via an enzymatically cleaved tetrapeptide
linker. In vitro functional assays demonstrated that DB-1305 was selectively bound to
Trop-2-positive cells and was endocytosed into the lysosomes, exhibiting
concentration-dependent cytotoxicity.

In vivo, treatment with DB-1305 resulted in strong antitumor activity in murine cell-derived
xenograft models using MDA-MB-468, COLO205 and DMS-53, with significantly higher
efficacy compared with Dato-DXd. The exposure levels of DB-1305 and P1021 had no
obvious gender difference and no apparent accumulation in monkeys and rats. It was well
tolerated in the GLP toxicity studies in Cynomolgus monkeys with the highest
non-severely toxic dose (HNSTD) of 80 mg/kg, which is significantly higher than HNSTD
of 30 mg/kg for Dato-DXd.
Figure 5. DB-1305 phase I
ESG401
ESG401, an innovative ADC co-developed by Escugen and Levena Biopharma, consists
of a humanized anti-Trop2 IgG1 monoclonal antibody coupled to the topoisomerase I
inhibitor SN-38 through a proprietary stable cleavable linker and was approved for clinical
use in China on July 21, 2021.

At ASCO 2023, Escugen reported preliminary study data from the first human study of
ESG-401. The data showed that of the 33 subjects with evaluable efficacy, 12 subjects
achieved PR with an ORR of 36.4% and 9 subjects achieved SD (including 4 subjects who
achieved SD lasting ≥24 weeks) with a DCR of 63.6%. In addition, the ORR was 66.7%
and DCR was 83.3% in the highest dose group; the ORR was 36.3% and DCR was 63.6%
in the effective dose TNBC patients; and the ORR was 61.5% and DCR was 76.9% in the
effective dose HR+/HER2-BC patients.
The incidence of study drug-related adverse events (TRAEs) was 94.3% (33/35), and the
incidence of grade 3 and higher TRAEs was 34.3% (12/35). The most common grade ≥3
TRAEs (≥10%) were decreased neutrophil count and decreased white blood cell count.
Preliminary findings suggest that ESG401 has an excellent safety profile, a favorable
adverse effect profile and that subjects can be treated long-term.
Figure 6. Preliminary results ESG401, source: reference [7]
BAT8008
BAT8008 is an ADC targeting Trop2 developed by Bio-Thera, consisting of a recombinant
humanized anti-Trop2 antibody linked to a toxic small molecule topoisomerase I inhibitor
by an in-house developed shearable linker. BAT8008 has highly potent antitumor activity
and the toxin small molecule has a strong bystander effect to overcome the heterogeneity

of tumor tissue. At the same time, BAT8008 has good stability and safety, with extremely
low release of toxin small molecules in plasma, reducing the risk of off-target toxicity.
At the AACR meeting, Li et al. reported that BAT8008 exhibited potent in vitro cell growth
inhibitory activity against Trop2-positive cells with an IC50 value of <1 nM. In an in vitro
bystander killing assay, medium with addition/transfer of BAT8008-treated Trop-2-positive
cells effectively inhibited the proliferation of Trop-2 negative cells, but not of
BAT8008-treated Trop-2 negative cells, suggesting a bystander killing effect of the
payload released in the medium.
In Trop-2-positive MDA-MB-468 and MX-1 xenograft mouse models, single doses of 1
and 2.5 mg/kg of BAT8008 inhibited tumor growth by 73% and 81%, respectively. In a
pancreatic BxPC-3 xenograft mouse model, BAT8008 also showed better tumor
suppressive activity than using Daiichi's ADC technology or Trodelvy's modified ADC.
Conclusion
Trop-2 protein is highly expressed in a variety of tumors, such as pancreatic cancer,
breast cancer, colon cancer, bladder cancer, oral squamous cell carcinoma and ovarian
cancer. It can promote the process of tumor cell proliferation, invasion, metastasis and
spread, and its high expression is closely related to the shortened survival and poor
prognosis of tumor patients. In addition, high expression of Trop-2 has been found to be
associated with more aggressive disease and poor prognosis in several cancers,
including breast cancer.
Therefore, the development of anti-tumor drugs targeting Trop-2 is of great importance
and has become a new target for the development of ADCs. Recently, Trop-2 ADCs have
received several major advances, including the approval of Trodelvy for the treatment of
triple-negative breast cancer (TNBC) and advanced uroepithelial carcinoma (UC), and
several other pharmaceutical companies have entered the clinical and preclinical phases.
It is believed that more targeted Trop2 drugs will be approved for marketing in the near
future.

As one of the research and development hotspots in the field of medicine, more than 100
ADCs are currently in different stages of clinical development, and there are hundreds of
ongoing clinical trials. Biopharma PEG, as a professional PEG derivatives supplier, is
dedicated to being your most reliable partner to provide chemical synthesis and
high-quality PEG linkers. We are committed to promoting the progress of your ADC
discovery and development projects.
References:
[1]
https://www.astrazeneca.com/media-centre/press-releases/2023/datopotamab-deruxteca
n-met-dual-primary-endpoint-of-progression-free-survival-in-patients-with-advanced-non-
small-cell-lung-cancer.html
[2]
https://www.astrazeneca.com/media-centre/press-releases/2023/datopotamab-deruxteca
n-combinations-showed-encouraging-tumour-responses-in-patients.html
[3]
https://www.onclive.com/view/real-world-outcomes-with-sacituzumab-govitecan-match-as
cent-in-single-center-study
[4] https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.9114?af=R
[5]
https://www.biospace.com/article/releases/bionecure-therapeutics-announces-fda-cleara
nce-of-investigational-new-drug-ind-application-for-bio-106-a-novel-trop2-adc-for-the-trea
tment-of-advanced-solid-tumors/
[6] https://www.ejcancer.com/article/S0959-8049(22)01041-3/fulltext
[7] https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.1100
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