MA06.09 Preliminary Safety, Efficacy Results of KN046 (Bispecific Anti-PD-L1/CTLA4) in Subjects With Rare Thoracic Tumors

Abstract

On day 12, CT guided local irradiation in a single high dose (dose rate: 3Gy/min) of the former tumor region, resembling IMRT in human patients, was applied. We monitored animal's health status daily and tumor growth every 3 days by BLI. Results: None of the animals, whether with radiotherapy alone or in combination with cis-fib, showed any signs of pulmonary side effects. None had reduced pulmonary functions, measured by increased breathing or the appearance of blue or white colored ears/extremities/eyes assuming desaturation. No weight loss was observed after 10Gy IR, either alone or in combination with cis-fib. Treatment with a single dose of 20Gy IR or cis-fib+20Gy IR caused weight loss on the day after treatment but all animals regained weight 2 days thereafter. No deterioration of body conditioning or activity score were observed in the immediate postinterventional phase. Regarding efficacy, we detected comparable tumor growth in animals treated with 10Gy IR compared to no IR (cis-fib) group. Thus, we decided to escalate to 20Gy after treating 6 animals/group. Three days after treatment with 20Gy IR (day 15), we detected a significant difference in tumor growth in IR alone compared to cis-fib+IR group (mean tumor growth (%) 539 vs 252; p¼0.04). On day 21, there was a significant difference in tumor growth between cis-fib vs cis-fib+IR treated tumors (mean tumor growth (%) 2295 vs 660; p¼0.01) (figure1). Conclusion:Irradiation alone and in combination with local intracavitary cis-fib application in rats is safe up to a dosage of 20Gy. The administration of local 20Gy radiotherapy in combination with cis-fib enhances tumor control while only minimally (and short term) affecting animal's well-being. These data suggest a promising effect of combined local treatment with cis-fib+IR for MPM.

Novel Bi-Specific Immuno-Modulatory Tribodies Potentiate T Cell Activation and Increase Anti-Tumor Efficacy

“…The novel tribodies could have some advantages with respect to BiTEs, such as: the ability to bind to three different targets [ 30 , 42 ]; higher molecular weight, that could achieve longer half-life in circulation, as previously reported for other tribodies [ 43 ]; and Fc-free format, that avoids the induction of nonspecific cytokine storms of different bispecific molecules including Fc, such as Catumaxomab, an anti-CD3/EpCAM used for the intraperitoneal treatment of malignant ascites. Other bispecific mAbs in clinical use or trials are: Cinrebafusp alfa (PRS-343), a bispecific fusion protein targeting both HER2/4-1BB on tumor cells and T cells, currently in phase I of clinical trial (NCT03330561) for HER2-positive tumor patients [ 14 , 15 , 16 ]; and KN046, an IgG1 bsAb targeting both PD-L1 and CTLA-4, currently in a phase I clinical trial (NCT03529526) on metastatic triple negative breast cancer [ 17 , 18 , 19 ]. However, both of these contain the Fc portion, and thus, could have higher nonspecific side effects and larger molecular weights than the novel tribodies.…”

“…A key structural feature of bsAbs is the presence/absence of the Fc region [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Fc-free bsAbs display better biodistribution into tumor tissues, higher potency, and less common incidence of immune-related adverse effects (irAEs) [ 19 ]; on the other hand, continuous intravenous infusion or structural modifications are needed to prolong their half-lives, such as fusion with polyethylene glycol or human serum albumin [ 20 ].…”

Research and Clinical Landscape of Bispecific Antibodies for the Treatment of Solid Malignancies

“…Interestingly, KN046 has been granted orphan drug designation for the treatment of patients with metastatic thymic epithelial tumors progressing on a platinum-based chemotherapy and is under evaluation in a phase II clinical trial (NCT04469725) [ 74 ]. Moreover, KN046 is currently being tested in more than ten tumor types, also in combination with KN026.…”

Development of Plant-Derived Bispecific Monoclonal Antibody Targeting PD-L1 and CTLA-4 against Mouse Colorectal Cancer

“…These bsAbs increased the T cell response in vitro , had stronger antitumor response in vivo , demonstrated lower cytotoxicity and equivalent activity to blocking antibodies in preclinical studies, resulting in an enhanced therapeutic index 6 , 7 . Furthermore, preliminary clinical evaluation of these bsAbs revealed acceptable safety, good tolerability, and promising antitumor efficacy in patients with advanced tumors of various types 8 , 9 , 10 , 11 . To date, several immune checkpoint bsAbs are being investigated in clinical trials 12 .…”