SHANGHAI – Alphamab Oncology Co. Ltd., of Suzhou, China, has kicked off a phase I study in Australia for KN-046, a PD-L1/CTLA-4, a potentially first-in-class bispecific that combines two domain antibodies fused with IgG Fc.

It has already been dosed in seven patients with advanced cancer and is on track to be studied in China next month. Going to Australia first will help Alphamab Oncology with its global ambitions for KN-046; patient data from Australia will be used to further applications outside of Asia.

PD-L1 and CTLA-4 are negative regulators of T-cell immune function. As single agents, the antibodies have been approved by regulators, and promising tests are underway to combine CTLA-4 candidates with PD-1/PD-L1-targeting drugs in a wide range of malignancies.

Bispecifics – a single antibody that hits two targets – are trickier than monoclonal antibodies to engineer and manufacture. Globally, there are less than a handful of bispecifics combining the more common PD-1 with CTLA-4. One contender with roots in China is Akeso Biopharma Inc., of Guangdong, which also is testing its bispecific in Australia.

KN-046, however, is the first to PD-L1/CTLA-4 bispecific to be tested in patients with various forms of advanced malignancy, and the aim is to be better than the combination of the two monotherapies, said Ting Xu, chairman and CEO of Alphamab Oncology.

"Our design for the PD-L1 and CTLA-4 bispecific is based on a PD-L1 domain antibody that targets the tumor microenvironment. PD-1 antibodies do not have this kind of targeting; they are all on the T cells, not on APC and tumor cells," Xu said.

"We positioned this bispecific to be the backbone of immuno-oncology 2.0, which means we are going to try to replace PD-1 and PD-L1 monotherapy," he added. "We feel there is the potential to have much better safety and efficacy."

Xu said the bispecific is based on best-in-class technology for both targets. The PD-L1 antibody used in the bispecific is based on Alphamab Oncology's KN-035, being studied in a phase III trial in China (with trials ongoing in the U.S. and Japan as well).

"We needed a really good building block for a bispecific. That is why we spent quite a few years to build a PD-L1 single-domain antibody and a proprietary CTLA-4 single-domain antibody with an improved safety profile," Xu said.

In earlier trials conducted by other companies, the combination of the two antibodies proved efficacious but led to undesirable levels of toxicity. Alphamab Oncology's gamble is that by hitting the tumor microenvironment, its bispecific will have fewer side effects compared with the existing approved CTLA-4 antibody, Yervoy (ipilimumab, Bristol-Myers Squibb Co.).

According to Xu, the bispecific CTLA-4 binding activity is significantly lower than the PD-L1 in the molecule. The CTLA-4 single-domain antibody chosen when formulating KN-046 has a different binding epitope than ipilimumab. Because of the low toxicity, KN-046 started dosing at 0.3mg/kg and is moving through to dosing at 3mg/kg.

Patients with late-stage cancers such as melanoma, triple-negative breast and lung cancer received the drug in Australia.

In China, a bridging study will be conducted before a large phase I 400-patient study can commence. There are plans to broaden the scope to possibly eight indications to include non-small-cell lung cancer and small-cell lung cancer.

Making elbow room in China's PD-1 field

KN-046 is part of Alphamab Oncology's strategy to carve out a niche in jam-packed field of close to 180 PD-1/PD-L1 monoclonal antibodies being developed in China. BMS' Opdivo and Merck & Co Inc.'s Keytruda (pembrolizumab) were only approved recently. (See BioWorld, June 27, 2018, and Aug. 18, 2018.)

It is estimated that at least another three or four domestic contenders will gain market approval by the end of 2018 or early 2019.

In terms of commercial viability, Xu is not alone in foreseeing a bloodbath. "I don't think the China market will be able to support more than 10 players, at the most, if they only have a regular PD-1 or PD-L1 antibody drug," he said.

While some biotechs are going for combinations of two drugs with the PD-1/PD-L1 as the cornerstone, such as Beijing's Beigene Ltd. and Suzhou's Cstone Pharmaceuticals Co., Alphamab is finding its own way. Its lead candidate, KN-035, is a PD-L1 administered via subcutaneous injection, the only one of its kind. Taking advantage of nanotechnology, the drug can be stored at room temperature. That opens up a patient group that otherwise may not be able to receive antibodies by intravenous infusion, as is the case with Opdivo and Keytruda. It also allows patients who are living longer to receive maintenance treatments from home.

The plan is to submit a biologics license application (BLA) in the fourth quarter 2019 for KN-035. Although arriving rather late in comparison to the leading China contenders in the PD-1/PD-L1 race, that may work in Alphamab Oncology's favor as more patients become aware of biologics in China but look for a more convenient way to take them.

China bispecifics and I-O 2.0

China has an increasing number of biotechs developing bispecifics.

Alphamab Oncology has a platform that has also generated a HER2-bispecific that recently got the green light for clinical testing in China. (See BioWorld, April 19, 2018.)

The company has invested in commercial-scale manufacturing to support the HER2 and PD-L1/CTLA-4 bispecific programs. Its Fc-based heterodimer bispecific platform is called CRIB (Charge Repulsion Induced Bispecific) and is designed to solve certain manufacturing issues. The CRIB platform allows bispecifics to be formed with the same format and size of a regular antibody. The focus is less on the cost-effectiveness of the bispecific and more on the effectiveness of the antibody.

Epimab Biotherapeutics Inc., of Shanghai, has its own bispecific platform, FIT-Ig, and has been developing its own candidates, as well as licensing out to the likes of Innovent Biologics Inc., of Suzhou. (See BioWorld Today, June 7, 2016.)

Meanwhile, Generon Corp. has the ITAB platform, Adagene Inc. calls its platform DPL and YZY Bio Co. Ltd. has a Ybody solution.

Alphamab Oncology – an offshoot

Alphamab started out early on as a contract research organization but has methodically developed its own pipeline.

To hone its focus on cancer treatments, Xu has created Alphamab Oncology and invested it with various assets and development ambitions. The plan, as it stands today, is to prepare the company to go public in the next year.

Alphamab Oncology has its work cut out for it, developing bispecific and monoclonal antibody platforms, raising series A financing and eventually making its way to the Hong Kong Stock Exchange in order to fund multiple clinical trials.

For global markets, Alphamab Oncology is open to licensing and partnerships for KN-046.

Meanwhile, parent Alphamab will remain a private research organization that survives on partnerships and grants and will continue its interest in non-oncology research and collaboration.