7:56 PM
 | 
May 03, 2018
 |  BC Innovations  |  Targets & Mechanisms

Solid hopes for T cell bispecifics

Will next-generation T cell bispecifics find their place in solid tumors?

As next-generation T cell bispecifics hit the clinic, demonstrating efficacy in solid tumors could earn them a place in the immuno-oncology tool kit alongside CAR T cells and checkpoint inhibitors.

T cell bispecific antibodies bring activated T cells into proximity with tumor cells to facilitate tumor killing, similar to the way CARs mobilize T cells to fight cancers. First-generation platforms have a CD3-binding domain linked to a tumor antigen-binding domain; next-generation platforms add a third domain to promote protein stability.

First-generation products Blincyto blinatumomab from Amgen Inc. and Removab catumaxomab from Trion Pharma GmbH have gotten off to a slow start, or have not lived up to expectations. Removab, which was approved for malignant ascites in 2009, was withdrawn from the U.S. market in 2013 and Europe in 2017 because it was not commercially viable.

Blincyto was approved for CD19-positive acute lymphoblastic leukemia (ALL) in 2014, and its label was expanded last month to include patients in remission with minimal residual disease (MRD).

Its sales are growing quickly but remain modest. Revenues for 2017 were $175 million, a 52% increase over 2016.

Developers of next-generation T cell bispecifics have made modifications to improve PK profiles and dosing, and have additional reasons to be optimistic about their place in the immunotherapy landscape.

For instance, preclinical studies suggest T cell bispecifics may penetrate solid tumors better than cell therapies and turn cold tumors hot, making them suitable for combinations with checkpoint inhibitors. And unlike most CAR Ts, which are autologous and must be manufactured to order for each patient, T cell bispecifics are off-the-shelf therapies that can be administered to any patient on demand.

According to BioCentury’s BCIQ database, at least 27 next-generation T cell bispecifics are in the clinic for cancer.

Of these, 16 are in Phase I or preclinical development, targeting 12 different antigens. Most are in development to treat solid tumors (see “Solid Showing”).

Table: Solid showing

At least 16 T cell bispecifics are in preclinical development or Phase I testing for solid tumors. The first glimpses of how bispecifics stack up against CAR T cell therapies will likely come from AMG 596, a next-generation Bispecific T Cell Engager (BiTE) that targets epidermal growth factor variant III (EGFRvIII) for brain cancer, which Amgen Inc. (NASDAQ:AMGN). is testing in Phase I. CARsgen Therapeutics Co. Ltd. has an EGFRvIII-targeting CAR, CAR-EGFR/EGFRvIII, in Phase I testing for brain cancer, and Novartis AG (NYSE:NVS; SIX:NOVN) also has a similar CAR, CAR-T-EGFRvIII, in Phase I for the same indication.

CEA-TCB from Roche (SIX:ROG; OTCQX:RHHBY), AMG 211 from Amgen, ERY974 from Chugai Pharmaceutical Co. Ltd. (Tokyo:4519) and APVO414 from Aptevo Therapeutics Inc. (NASDAQ:APVO) also target tumor antigens that are targeted by CAR T programs in Phase I, but the bispecifics and CAR Ts are in development for different tumor types. (A) AMG 211, a first-generation BiTE from Amgen, is no longer in active development. Source: BCIQ: BioCentury Online Intelligence, company websites, ClinicalTrials.gov

CompanyProductTumor antigen Cancer typeDevelopment stageMilestone
Roche (SIX:ROG; OTCQX:RHHBY)CEA-TCBCarcinoembryonic antigen (CEA)Colorectal cancer, solid tumorsPhase IReported May 2017
Amgen Inc. (NASDAQ:AMGN)/AstraZeneca plc (LSE:AZN; NYSE:AZN)AMG 211CEAGastrointestinal adenocarcinomaPhase ICompleted Dec 2017 (A)
MacroGenics Inc. (NASDAQ:MGNX)MGD009B7-H3 (CD276)Solid tumorsPhase IPrimary completion Dec 2018

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