IgG-based B7-H3xCD3 bispecific antibody for treatment of pancreatic, hepatic and gastric cancer

Abstract

T cell-based immunotherapy has significantly improved treatment options for many malignancies. However, despite these and other therapeutic improvements over the last decades, gastrointestinal cancers, in particular pancreatic, hepatic and gastric cancer, are still characterized by high relapse rates and dismal prognosis, with an accordingly high unmet medical need for novel treatment strategies. We here report on the preclinical characterization of a novel bispecific antibody in an IgG-based format termed CC-3 with B7-H3xCD3 specificity. In many cancer entities including pancreatic, hepatic and gastric cancers, B7-H3 (CD276) is overexpressed on tumor cells and also on the tumor vasculature, the latter allowing for improved access of immune effector cells into the tumor site upon therapeutic targeting. We demonstrate that CC-3 induces profound T cell reactivity against various pancreatic, hepatic and gastric cancer cell lines as revealed by analysis of activation, degranulation and secretion of IL2, IFNγ as well as perforin, resulting in potent target cell lysis. Moreover, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. Together, our results emphasize the potential of CC-3, which is presently being GMP-produced to enable clinical evaluation for treatment of pancreatic, hepatic and gastric cancer.

An Fc-modified monoclonal antibody as novel treatment option for pancreatic cancer

“…Another approach which is frequently pursued are B7-H3 targeting CAR T cells, which are being evaluated in various tumor entities including advanced pancreatic carcinoma (NCT04897321, NCT05211557, NCT05341492, NCT04483778, NCT05323201, NCT05241392, NCT05474378, NCT03198052, NCT04185038, NCT05366179, NCT04670068, NCT05143151). Furthermore, various B7-H3 targeting approaches are currently under preclinical evaluation like, but not limited to a B7-H3 TriKE (GBT-5550), camel nanobody-based CAR T cells ( 57 ), a dual nanobody NK cell engager ( 58 ) and bispecific antibodies ( 59 – 62 ).…”

New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3

“…B7-H3-targeted CAR-T cells are currently being tested in patients with advanced PAC in a phase I/II clinical trial (NCT05143151). More recently, Lutz et al described notable anti-tumor efficacy of a B7-H3Xcd3 bispecific antibody in PAC, as evidenced by enhanced T-cell activation and secretion of IL-2, IFN-g, and perforin, which resulted in tumor cell lysis [ 90 ]. Lastly, vobramitamab duocarmazine is currently being tested in combination with lorigerlimab for patients with PAC in a phase I study (NCT05293496).…”

“…Significant increase in CD4 + and CD8 + T-cell proliferation was observed upon treatment with CC-3 in co-cultures of GC cells and T-cells ( p = 0.01 and p = 0.001, respectively). Furthermore, significant increase was shown in secretion of IL-2, IFNγ, IL-10, and TNF that resulted in enhanced GC cell lysis ( p < 0.0001) [ 90 ]. Combined inhibition of HER2 and B7-H3 using the humanized anti-HER2 mAb trastuzumab and an anti-B7-H3 mAb yielded better tumor control than either monotherapy [ 99 ].…”