Bispecific Interest Reaches A Crescendo

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Includes: ALPMF, ALPMY, TKPHF, TKPYY
by: EP Vantage

Crescendo Biologics has received an endorsement of its Humabody drug development platform in the form of a deal with Takeda (OTCPK:TKPHF) (OTCPK:TKPYY) worth up to $790m. But with only $36m of this coming up front, the Japanese pharma giant is taking a cautious stance.

If the Humabody technology lives up to Crescendo’s claims, though, Takeda could soon become the latest player to enter the bispecific arena, and Crescendo says it could also be used develop multi-specific products. The collaboration will home in on cancers with a high unmet need – Crescendo chief executive Peter Pack tells EP Vantage that these will originate from Takeda.

Mr Pack is quick to point out that the company’s technology, which relies on transgenic mice, does not produce antibodies. Instead, the UK-based company’s fully-human Humabodies are made up of smaller antibody fragments known as the VH domain – essentially the antigen-binding section.

“This is the smallest possible immunoglobulin – it’s around a tenth of the size of a full antibody,” he says. This should mean the molecules can rapidly penetrate tissue and tumors and clear quickly to reduce systemic toxicity.

Bispecific

Perhaps more interestingly, this small size also means that these VH domains can be combined in various ways to create bi- or multi-specific products, a concept that Mr Pack compares with building with Lego bricks.

This approach could be used to hit multiple targets. For example, in oncology it could either act on two epitopes on the same receptor, which could increase the overall effect, or target different receptors to both stimulate the patient’s immune system and remove its brakes, for instance.

In this way Crescendo’s approach could be similar to conventional immuno-oncology drug combinations, which various companies are investigating following the success of PD-1/PD-L1 inhibitors.

However, there could be advantages of combining the targets into one Humabody product versus using two antibodies, Mr Pack believes – not least because the size of antibodies can inhibit their penetration into the tumor.

Bispecific antibodies are having a bit of a moment, with Amgen’s recent purchase of a BCMA-targeting product from Boehringer highlighting a crowded early-stage pipeline (Behold the son of Blincyto, September 2, 2016).

Mr Pack claims that Crescendo has gone a step further by producing tri- and tetra-specific Humabodies, something he says most of its competitors cannot do.

Humabody-drug conjugates

In addition, the Humabodies can be customized in other ways, for example adding a toxic payload to create Humabody drug conjugates (HDCs).

This would work similarly to existing antibody-drug conjugates like Roche’s Kadcyla, allowing more targeted cancer therapy, but with the advantages of Humabodies over traditional antibodies, such as rapid tumor penetration, which could lead to an increased tumor-to-blood ratio and better toxicity profile.

The Takeda deal encompasses both the immuno-oncology space and HDCs. The projects are at the initial discovery stage and Mr Pack declined to speculate on when they might go into the clinic.

While this is Crescendo’s first large partnership with a major pharma player, it has already received investment from Astellas’ (OTCPK:ALPMF) (OTCPK:ALPMY) venture capital arm, and is also collaborating with companies developing payloads and linkers for use in its HDC projects.

As well as seeking partnerships, Crescendo is developing its own pipeline products, including an HDC project in prostate cancer, and one in immuno-oncology for an undisclosed indication. Both are at the preclinical stage.

The Takeda deal is early-stage, but suggests that Crescendo’s technology is promising. It will be a while, however, before Mr Pack’s claims can be proven.

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