With five antibody-drug conjugates (ADC) having received approval from the United States Food and Drug Administration (FDA) and other regulators around the world and nearly 60 innovative drug development companies involved in the development of these targeted agents, the number of ADCs entering the clinic is rapidly growing.

While this may be the case of HER2-targeting ADCs, growth has especially been noted the development of ADC-targeting B7-H3 and TROP2.

In late October 2019 Daiichi Sankyo announced that its DS-7300, B7-H3 (B7 homologue 3) targeting antibody-drug conjugate entered first-in-human clinical phase I/II trials for the treatment of patients with advanced solid malignant tumors. [A] The clinical trial is conducted in collaboration with Sarah Cannon Research Institute, one of the world’s leading clinical research organizations conducting community-based clinical trials throughout the United States and United Kingdom.

DS-7300 is the fourth antibody-drug conjugate in clinical development.  The investigational agent uses Daiichi Sankyo’s proprietary DXd technology and was designed to target and deliver chemotherapy inside cancer cells that express the B7-H3 protein, which is frequently and highly overexpressed in various types of cancers, including lung, head and neck, esophageal, prostate, endometrial and breast cancers, and has been associated with disease progression and poor prognosis in many tumor types. [1][2]

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B7-H3 also known as CD276, is a transmembrane protein, an immune checkpoint, belonging to the B7 family which plays a role in tumor growth as well as in immune response. [1][2].

Another B7-H3 targeting ADC s MacroGenics’ MGC018 (hMG.Ab.02–DUBA ADC). This investigational agent links a humanized B7-H3 antibody to a potent DNA alkylating payload, a synthetic duocarmycin analog prodrug known as seco-duocarmycin-hydroxybenzamide-azaindole (seco-DUBA), via a valine-citrulline cleavable peptide linker.

MGC018 binds to the minor groove of DNA and subsequently cause irreversible alkylation of DNA. This disrupts the nucleic acid architecture, which eventually leads to tumor cell death. The drug is currently being evaluated in a Phase I dose escalation study. The linker-payload was licensed from Synthon Biopharmaceuticals.

Preclinical Development of a Duocarmycin-based Antibody-Drug Conjugate Targeting B7-H3 for Solid CancerThomas Son, Juniper A. Scribner, Jeff Hooley, Michael Chiechi, Pam Li, Tim E. Hotaling, Anushka De Costa, Yan Chen, Francine Chen, Bhaswati Barat,Ling Huang, Valentina Ciccarone, Timur Gaynutdinov, James Tamura, Scott Koenig, Syd Johnson, Paul A. Moore, Ezio Bonvini, Deryk Loo
Poster presentation during the 2017 annual meeting of the American Association of Cancer Research demonstrating preclinical Development of a Duocarmycin-based Antibody-Drug Conjugate Targeting B7-H3 for Solid Cancer. Thomas Son, Juniper A. Scribner, Jeff Hooley, Michael Chiechi, Pam Li, Tim E. Hotaling, Anushka De Costa, Yan Chen, Francine Chen, Bhaswati Barat,Ling Huang, Valentina Ciccarone, Timur Gaynutdinov, James Tamura, Scott Koenig, Syd Johnson, Paul A. Moore, Ezio Bonvini, Deryk Loo. Click here to enlarge.

Initial preclinical results presented in a poster presentation during the 2017 annual meeting of the American Association of Cancer Research (AACR), demonstrated a favorable preclinical profile of MGC018 with strong reactivity toward tumor cells and tumor-associated vasculature, limited normal tissue reactivity, potent cytotoxicity in vitro and antitumor activity in vivo toward a range of B7-H3-expressing tumor cell lines representing several cancer types.

TROP2 Targeting ADCs
Daiichi Sankyo’s DS-7300 was engineered using the company’s proprietary  technology, DAR-controlled conjugation, to create a drug-to-antibody ratio (DAR) of four. The same technology was also used to develop DS-1062, Daiichi Sankyo’s TROP2 ADC under clinical development in patients with Non Small Cell Lung Cancer (NSCLC) who have failed standard of care, including immune checkpoint inhibitors.

TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is highly expressed on several types of solid tumors, including NSCLC.[3][4] Researchers have recognized TROP2 as a promising molecular target for therapeutic development in various types of malignancies, including NSCLC.[4] Over-expression of TROP2 has been associated with increased tumor aggressiveness and decreased survival in several cancers.[5] High TROP2 expression was identified in 64% of non-small cell adenocarcinomas and 75% of non-small cell squamous cell carcinomas in one study.[3] Currently, no TROP2 targeting therapy is approved for NSCLC or any cancer.

In addition to Daiichi Sankyo’s DS-1062, KLUS Pharma, a subsidiary of Kelun Pharmaceuticals (Sichuan Chengdu, China), is developing a new TROP-2 targeting antibody-drug conjugate called SKB264.

Following preclinical studies, showing SKB264 good results in TROP-2 positive triple negative breast cancer (TNBC), gastric cancer and significant anti-tumor activity in animal models of lung cancer and colorectal cancer, the drug is now entering first-in-human clinical trial for the treatment of locally advanced/metastatic solid tumors patients in phase I/II. [B]

SKB264 is Klus Pharma’s second ADC which received Investigational New Drug (IND) approval from FDA after A166, which targets HER-2 and entered clinical trials in May 2018. [C]

KLUS Pharma claims that its development program includes more than ten novel therapeutic monoclonal antibodies, antibody-drug conjugates and bispecific antibody drugs for the treatment of advanced cancers.s

Other TROP2 ADC’s
The other TROP2 ADCs include Immunomedics’ sacituzumab govitecan, Daiichi Sankyo’s DS-1062 and Biothera’s BAT8003.

Sacituzumab govitecan
Sacituzumab govitecan received Breakthrough Therapy designation from the FDA for the treatment of patients with triple-negative breast cancer (TNBC) who have failed prior therapies for metastatic disease. The investigational drug also received Fast Track designation for patients with TNBC, and for patients with small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) and orphan drug by the FDA for the treatment of patients with SCLC or pancreatic cancer in the U.S. and by the European Medicines Agency (EMA) for the treatment of patients with pancreatic cancer in the European Union.

Over the last 9 months, the company has made significant progress in resolving important manufacturing and clinical problems. As a result of this work the company expect to be on target to resubmit the Biologics License Application (BLA) for sacituzumab govitecan in late-stage metastatic triple-negative breast cancer (mTNBC) in patients who have received at least two prior therapies for metastatic disease to the FDA in late November or early December, 2019.

According to the company’s Executive Chairperson, Behzad Aghazadeh, Ph.D, the company is “…well-positioned for a pre-approval inspection following our resubmission of sacituzumab govitecan…”

BAT8003, a Trop2-targeted antibody-drug conjugate being developed by Biothera (Guangzhou, China), uses an anti-Trop2 IgG1 antibody engineered for site-specific conjugation, a novel uncleavable linker, and a potent maytansine derivative as a payload.

The linker and the payload of the investigational agent are conjugated via a stable thioether bond to form Batansine (3AA-MDC) before being conjugated to the anti-Trop2 antibody.

BAT8003 is based on the company’s proprietary ADC technology. In addition, the investigational agent is also glycoengineered by afucosylation of the Fc region to enhance its antibody-dependent cell-mediated cytotoxicity (ADCC) effect. The indications for BAT8003 are mainly on Trop2-positive advanced solid tumors, including breast cancer, non-small cell lung cancer and urothelial carcinoma.

In vitro pharmacodynamics showed that BAT8003 possesses strong inhibitory effects on breast cancer, lung cancer and gastric cancer cells with high expression of Trop2. In vivo pharmacodynamics have demonstrated that BAT8003 significantly inhibited the growth of Trop2 overexpressed gastric and breast cancer tumors in a mouse model at a dose of 5 mg/kg or more with good safety.

BAT8001, Biothera’s first antibody-drug conjugate, targets HER2. This investigational drug covalently links a humanized anti-HER2 antibody, via a stable linker, to a maytansine derivative payload. This drug is in Phase III clinical trials for the treatment of HER2-positive, metastatic breast cancer who previously received trastuzumab separately or in combination.[D]

Clinical Trials
[A] Study of DS-7300a in Participants With Advanced Solid Malignant Tumors – NCT04145622
[B] A Phase I-II, First-in-Human Study of SKB264 in Patients With Locally Advanced/Metastatic Solid Tumors Who Are Refractory to Available Standard Therapies – NCT04152499
[C] Study of A166 in Patients With Relapsed/Refractory Cancers Expressing HER2 Antigen or Having Amplified HER2 Gene – NCT03602079
[D] A Phase I Clinical Trial of BAT1306 and BAT8001 Injection in Patients With Solid Tumor – NCT04151329.

[1] Zhang X, Fang C, Zhang G, Jiang F, Wang L, Hou J.Prognostic value of B7-H3 expression in patients with solid tumors: a meta-analysis. Oncotarget. 2017 Sep 21;8(54):93156-93167. doi: 10.18632/oncotarget.21114.
[2] Castellanos JR, Purvis IJ, Labak CM, Guda MR, Tsung AJ, Velpula KK, Asuthkar S. B7-H3 role in the immune landscape of cancer. Am J Clin Exp Immunol. 2017 Jun 15;6(4):66-75. eCollection 2017.
[3] Inamura K, Yokouchi Y, Kobayashi M, Ninomiya H, Sakakibara R, Subat S, Nagano H, Nomura K, Okumura S, Shibutani T, Ishikawa Y. Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes. Oncotarget. 2017 Apr 25;8(17):28725-28735. doi: 10.18632/oncotarget.15647. [Pubmed][Article]
[4] Zaman S, Jadid H, Denson AC, Gray JE.Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019 Mar 1;12:1781-1790. doi: 10.2147/OTT.S162447. eCollection 2019.[Pubmed][Article]
[5] Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015 Mar;6(3-4):84-105. [Pubmed][Article]

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