Silverback Therapeutics gets $78M boost to 'reconceptualize' antibody-drug conjugates
The resurgence of antibody-drug conjugates (ADCs), in which a cancer-killing toxin is attached to a specific antibody using a biodegradable linker, has offered the thriving field of oncology another potent weapon in the fight against cancer. But what if this trojan horse technology could be tweaked to link immune-stimulatory agents — as opposed to cytotoxic payloads — to monoclonal antibodies?
Silverback Therapeutics, which has long stayed mum about its technology platform, on Wednesday mapped its mission to use the strategy to target immunologically “cold” tumors — and now has a fresh capital injection of $78.5 million to make its case.
“The ADC category has been used successfully in the past and, of course, of late has had a renaissance with different payloads that are still cytotoxic, and we kind of reconceptualized the class in terms of its ability to localize small molecules that can be used to modulate powerful biologic pathways that are not necessarily cytotoxic,” clinical oncologist and Silverback CEO Peter Thompson told Endpoints News.
The Seattle, Washington-based company’s lead drug — SBT6050 — is an antibody-drug conjugate that delivers a heavy payload (in this case, TLR8 agonist) to HER2-expressing tumors. An application to test the drug in humans is expected to be filed in the first half of 2020, Silverback CSO Valerie Odegard said.
“It is well known that there are a lot of myeloid cells in tumors, even tumors that have been classically defined as being immunologically cold, which is actually just a reference to the fact that they don’t have T cells, they have myeloid cells,” she noted. “However, when those myeloid cells are activated, they have a number of mechanisms that they unleash that directly kill tumor cells. TLR8 is the innate immune receptor expressed in human myeloid cells, and the ability then to systemically deliver an agent, whose activity is localized to the site of the tumor and only activates myeloid cells in the tumor is a very exciting therapeutic.”
Existing ADCs are designed to deliver cytotoxic payloads such as chemotherapies to cells expressing the antigen target, but Silverback’s technology has another perk — it is engineered to work in a setting where only a fraction of the cells in the tumor need to express the target antigen.
“Unlike cytotoxic ADCs where you need, by and large, homogeneous expression, for example, of HER2 tumor targets in order to get appropriate target coverage on the tumor cells in order to kill them — it’s a very different mechanism here,” said Odegard, who previously worked with Juno Therapeutics.
With SBT6050, tumor cell destruction is possible even with heterogeneous HER2 expression, where only a fraction of the tumor cells — even as low as 25% — express HER2, she explained.
For Thompson, that ability is imperative for the broad population of HER+ expressing cancers the company plans to target.
“Being able to have a therapeutic modality that has significant potency and offers the opportunity for profound single-agent efficacy in a setting where only a fraction of the cells in the tumor need to express the target antigen gives us great confidence going into the clinic,” he said.
The drug’s safety profile offers another advantage, the executives suggested.
“Systemic administration of TLR agonists has been tried in the past, but thwarted by systemic toxicities that are engendered by the fact that you have a ton of myeloid cells all over the place, and in a nonspecific manner activating all of them is very difficult for the host to tolerate,” noted Thompson, who also serves as a private equity partner at OrbiMed, where the technology was created.
“Being able to localize these therapies to the sites of disease … in kind of a site-dependent context and being able to activate these mechanisms allows you to access the power of these systems, without the systemic toxicities,” he added.
Without delving into specifics, Thompson said the company is looking to address HER2 expressing cancers beyond the breast, including lung and colon. Eventually, the approach could also be used to address diseases such as chronic viral infections and fibrotic diseases, he said.
Back in 2018, the company raised $47.5 million for its A round, led by OrbiMed, with participation from Celgene and Alexandria. This new Series B haul was led by U.S. Venture Partners, with participation from new investors including Nextech Invest, Hunt Investment Group, Pontifax Venture Capital, Colt Ventures LP, and NS Investment. Existing investors — OrbiMed, Bristol Myers Squibb (which has swallowed Celgene) and Alexandria — all also jumped in.
The company is named Silverback in reference to the title given to the leader of a mountain gorilla troop. “We’re the 800-pound gorilla in a new field that we’ve created,” Thompson quipped.
The field of ADCs that uses cytotoxic payloads is also fairly hefty. Roche’s ADC Kadcyla generated blockbuster sales in 2019; Seattle Genetics’ Padcev was approved late last year and other armed antibodies partnered with Genmab and Takeda in the pipeline; Daiichi Sankyo’s AstraZeneca-partnered Enhertu, touted to generate billions in peak sales, was approved by the FDA months ahead of schedule in 2019 and data that could expand the use of the therapy has also been published. Other companies in the space include the aptly named ADC Therapeutics, Iconic Therapeutics, and Sutro Biopharma.
Social image: Peter Thompson, Silverback Therapeutics (OrbiMed Advisors Photo)