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)

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