It’s no secret that antibody therapies are gaining ever-increasing popularity in the pharmaceutical industry. Worth a mere 0.3 billion USD in 1997, the global antibody therapeutics market has already seen a rapid increase in value to approximately 246 billion USD in 2024. Current predictions indicate that this increase will continue, with the market estimated to reach a massive 685 billion USD by 2034.
Driving this impressive growth is the consistently demonstrated outstanding efficacy and safety of antibody therapeutics in the treatment of several major diseases, resulting in an unrelenting demand for the generation of new, highly specific molecules.
One such molecule is the anti-HER2 biparatopic antibody, zanidatamab (trade name Ziihera®), which received FDA approval for the treatment of adults with previously treated, unresectable or metastatic HER2-positive biliary tract cancer (BTC) in November last year. This approval represents the first for the class of biparatopic antibodies, opening up exciting new opportunities for future drug development.
From zero to Ziihera®
Unlike ‘classic’ bispecific antibodies, which simultaneously bind two different target antigens, biparatopic antibodies (bpAbs) such as zanidatamab are characterised by their specificity for two unique, non-overlapping epitopes on the same target antigen. This ‘dual binding’ of a given target antigen affords bpAbs many potential advantages; these may include increased binding affinity, improved target specificity, greater receptor internalisation/downregulation, and reduced likelihood of disease resistance.
However, despite biparatopic binding being established 30 years ago, only recent technological advances have enabled generation of these antibodies with sufficient quality for development into therapeutics. Production of a clinical candidate involves numerous design considerations, including choice of epitope, format and developability. The field offers increasingly sophisticated solutions to some of the issues, but the selection of the right solution in a particular biological context remains challenging.
Zymeworks’s zanidatamab (Ziihera®), which is being developed under license by Jazz Pharmaceuticals and BeiGene, Ltd, targets and binds two non-overlapping epitopes on HER2, a tumour associated antigen which stimulates growth of cancer cells. This dual binding activity is reported to drive several anti-tumour mechanisms including (i) HER2 signal blockade, (ii) attraction of cytotoxic immune cells, and (iii) promotion of HER2 receptor internalisation to downregulate its expression on the tumour cell surface.
The recent FDA approval of zanidatamab for use in BTC patients was based on the multicentre, single-arm, phase 2b clinical trial, HERIZON-BTC-01 (NCT04466891), which achieved over 30% tumour shrinkage in 41% of patients. Results from a phase 3 clinical trial in first-line HER2-positive gastroesophageal adenocarcinoma patients are expected in the second quarter of 2025. This trial (HERIZON-GEA-01) aims to compare the efficacy and safety of zanidatamab plus chemotherapy treatment, either with or without tislelizumab (an antibody which prevents cancer cells from ‘switching off’ the patient’s immune cells), to the current standard care.
Pipeline biparatopics
Hot on the tail of Zymework’s recent FDA approval, other biparatopic antibodies are already undergoing clinical trials. One example is Anbenitamab (KN026).
Developed by Alphamab Oncology, Anbenitamab is derived from anti-cancer drugs trastuzumab and pertuzumab, and, like zanidatamab, is directed against two distinct epitopes on HER2. Entering clinical trials in 2018, this anti-HER2 biparatopic has so far demonstrated good safety and tolerability profiles in patients with advanced metastatic breast cancer, HER-2 expressing gastric cancers and gastro-esophageal junction cancers.
Alphamab have further developed an antibody-drug conjugate comprised of Anbenitamab linked to a topoisomerase I inhibitor (JSKN003). The conjugate works by binding HER2 on the surface of tumour cells and subsequently releasing the linked inhibitor to promote accumulation of DNA damage and tumour cell death. In the ADC format, biparatopic targeting offers the potential for high affinity binding and better internalisation, leading to improved safety and efficacy. Current clinical data for JSKN003 suggests promising results, especially for patients with advanced HER2-expressing solid tumours, platinum-resistant ovarian cancer and HER2-expressing breast cancer.
Concluding remarks
The advance of biparatopic antibodies through the clinical trial process represents a huge step forward in precision medicine, confirming for the first time the applicability of biparatopic antibodies to clinical scenarios. With more biparatopic candidates currently in development, this novel class of antibodies has the potential to transform treatment landscapes across multiple diseases.
We expect to see increased numbers of patent filings to this technology, reflecting the growing interest in this space. The complex challenges involved in developing a bpAb with clinical potential can be reflected in a strong patentability position. As always, it will be important to understand the story behind the structure at the time the patent is drafted, to give the best chance of obtaining a suitable scope of patent protection.
