MRG004A, an antibody-drug conjugate targeting human tissue factor to treat solid tumors, has entered clinical trials in the United States.  The investigational agent, being developed by Shanghai Miracogen, a fully owned subsidiary of Lepu Biopharma.

In an open-label, multi-center, Phase I/II Dose Escalation, and Expansion Study investigators will assess the safety, tolerability, anti-tumor activity, and pharmacokinetics of MRG004A in patients with tissue factor positive advanced or metastatic solid tumors. All patients participating in the dose-escalation phase (Part A) and dose-expansion phase (Part B) will be administrated MRG004A on Day 1 of every 3 weeks (21-day cycle).

The primary outcome measures include Maximum Tolerated Dose (MTD), Recommended Phase II Dose (RP2D), Objective Response Rate (ORR) and Adverse Events (AEs).  The secondary outcome measures for the trial include Duration of Response (DoR), Disease Control Rate (DCR), Progression-free Survival (PFS), Overall Survive (OS), Pharmacokinetics (PK; including Cmax, Tmax, AUClast) and Incidence of anti-drug antibody (ADA).

Tissue Factor
The investigational agent targets Tissue Factor (TF) a 47-kDa membrane-bound cell surface receptor. It is also known as thromboplastin, coagulation factor III (fIII) or CD142. TF is highly expressed on tumor cells and in the tumor.[1]

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Research has shown that there is a strong relationship between TF and cancer. Many cancer cells express high levels of both full-length TF and alternatively spliced (as) TF. Clinical studies have shown that the expression of TF in cancer is associated with poor prognosis. Furthermore, a high level of TF expression in tumors is associated with metastasis in a variety of cancer types, including colorectal cancer, gastric cancer, and pancreatic cancer.[1]

MRG004A is comprised of a human monoclonal antibody against TF and is conjugated to a cytotoxic agent. The agent is internalized after binding to tissue factor on tumor cells, after which the cytotoxic agent is released; this can result in targeted tumor cell death.

The novel ADC, conjugated using N-glycan residing at asparagine-297′ GlycoConnect™ site-specific conjugation technology, was selected for clinical development based on highly competitive efficacy and tolerability in preclinical studies compared to conventional ADC technology.

The Netherlands-based Synaffix focuses on commercializing its clinical-stage platform technology for the development of antibody-drug conjugates (ADCs) with a best-in-class therapeutic index.

The GlycoConnect technology easily matches payload potency with the most appropriate drug-antibody ratio (DAR). Starting from a native, nonengineered, antibody, a chemoenzymatic protocol allows for the highly controlled attachment of any given payload to the N-glycan residing at asparagine-297. Based on a two-step process, which includes enzymatic remodeling (trimming and tagging with azide), followed by ligation of the payload based on copper-free click chemistry, the technology can be used with any IgG isotype irrespective of glycosylation profile.[2]

Licensing agreements
Today, more than 10 ADCs are currently being developed using the company’s technology and it is the 3rd ADC built with GlycoConnect™ ADC technology to enter the clinic.

Synaffix signed a licensing agreement with Shanghai Miracogen, a Chinese biotechnology company with a clinical-stage pipeline of ADCs, in 2019. This major development has triggered a milestone payment to Synaffix.

“We have been very pleased with our collaboration with Synaffix and the data that we generated with ADCs built with its outstanding ADC technology. MRG004A has demonstrated the potential to become a best-in-class TF-targeted ADC and to address the high unmet medical need for patients,” said Mary Hu, Chief Executive Officer of Miracogen and Co-Chief Executive Office of Lepu Biopharma.

“This is an important milestone in our collaboration and we look forward to continuing our successful partnership as Miracogen develops multiple best-in-class ADC product candidates using our technology,” added Peter van de Sande, Chief Executive Officer of Synaffix.

There are now 3 ADCs that were built with Synaffix’s ADC technology in clinical development. We have now announced 6 collaborations that we have established with biotech and pharma partners around the world and more than 10 ADCs are being developed under those license agreements.” Van de Sande concluded.

In the last few months, Synaffix has signed significant agreements with Kyowa Kirin, a global specialty pharmaceutical company; ProfoundBio, an emerging oncology biotherapeutics company; and Innovent Biologics, a leading biopharmaceutical company developing innovative medicines for the treatment of major diseases. These come in addition to preexisting collaborations with ADC Therapeutics, Mersana Therapeutics and Shanghai Miracogen

Clinical trials
A Study of MRG004A in Patients With Tissue Factor Positive Advanced or Metastatic Solid Tumors – NCT04843709

[1] Hisada Y, Mackman N. Tissue Factor and Cancer: Regulation, Tumor Growth, and Metastasis. Semin Thromb Hemost. 2019 Jun;45(4):385-395. doi: 10.1055/s-0039-1687894. Epub 2019 May 16. PMID: 31096306; PMCID: PMC6546519.
[2] Van Geel R, Wijdeven MA, Heesbeen R, Verkade JM, Wasiel AA, van Berkel SS, van Delft FL. Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of Native mAbs Provides Homogeneous and Highly Efficacious Antibody-Drug Conjugates. Bioconjug Chem. 2015 Nov 18;26(11):2233-42. doi: 10.1021/acs.bioconjchem.5b00224. Epub 2015 Jun 10. PMID: 26061183.

Featured Image: Scientist holding a test tube in his laboratory. Courtesy: © 2010 – 2021 Fotolia/Adobe. Used with permission.

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