On December 8, 2021 GT Biopharma, Inc. (the "Company") (NASDAQ: GTBP), a clinical stage immuno-oncology company focused on developing innovative therapeutics based on the Company’s proprietary natural killer (NK) cell engager, TriKE protein biologic technology platform, reported that the Company’s mini-poster presentation abstract is now broadly available on the European Society for Medical Oncology ("ESMO") Immuno-Oncology ("IO") Congress 2021 abstracts webpage (Press release, GT Biopharma, DEC 8, 2021, View Source [SID1234596627]). The congress is being held from December 8-11, 2021, in Geneva Switzerland.
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"B7-H3 is a checkpoint molecule under intense investigation as an immune therapy target for solid and hematologic tumors. These proof of concept data via in vivo animal models validates GTB-5550’s candidacy for further investigation, noted Dr. Gregory Berk, President of R&D, Chief Medical Officer and Interim Chief Executive Officer. GT BioPharma’s diverse but focused pipeline of TriKE Nanobodies are highly targeted natural killer cell engagers, resulting in potent activation, proliferation, and persistence of the patient’s NK cells, without activation of T-cells, which are often responsible for the side effects of T-cell directed therapies. As such, we look forward to continuing the Company’s progress in the new year including the advancement of GTB-3650, second-generation TRIKE for patients with relapsed/refractory Acute Myelogenous Leukemia (AML) and high-risk Myelodysplastic Syndrome (MDS)."
The study was conducted by Dr. Jeff Miller’s lab, University of Minnesota where functional assays were conducted with various ovarian, prostate, and hematologic malignancy cell lines with varying levels of B7H3 expression from none to very high levels. Dr. Miller’s lab previously showed that dual camelid nanobody tri-specific killer engager (TriKE) (GTB-5550) specifically bound B7-H3 on PC3/C4-2 prostate cancer (PCa) cells and activated peripheral blood (PB) NK cells. We have since developed a dual camelid bispecific killer engager (BiKE) targeting B7-H3 and show that both GTB-5550, which harbors wild-type IL-15, and BiKE display broad activity against B7-H3-expressing tumors. Compared to monomeric IL-15, GTB-5550 shows CD16-dependent metabolic activation of NK cells.
Presentation highlights from the mini-poster titled, "Novel B7-H3 Targeting Dual-Nanobody NK Cell Engagers Display Robust Activity" include:
Study Background
BiKE and GTB-5550 were manufactured in a mammalian expression system and purified from supernatants.
Models were used to evaluate how the BiKE and GTB-5550 induce NK cell degranulation (CD107a) and interferon gamma production through a variety of cell lines including PCa cells harboring enzalutamide resistance with divergent mechanisms including 22RV1 (androgen ligand-independent AR-V7 splice variant) as well as a spontaneously resistant LNCaP model (AR hyper activation), as well as a CREB5 overexpressing (epithelial to mesenchymal transition) LNCaP model.
Metabolic stimulation was measured in NK-92 cell lines.
PB NK cells were robustly activated, compared to controls, when treated with GTB-5550 or BiKE and cultured with enzalutamide resistant PCa, osteosarcoma (U2OS, SaOS2), rhabdomyosarcoma (RH30), ovarian carcinoma (MA148, OVCAR8), AML (MV4;11, THP-1) and multiple myeloma (MM1S) cell lines.
GTB-5550 was approximately 2 times more potent than NCI IL-15 in terms of metabolic stimulation of CD16+ NK-92 cells, but not CD16- NK-92 cells. Spheroid killing assays and deeper metabolic analyses are in progress.
Results of the Study
The data demonstrated that the novel dual camelid nanobody BiKE and GTB-5550 induce NK cell activation against a broad spectrum of tumors expressing B7-H3. Furthermore, B7-H3 is expressed at high levels on prostate cancer cell lines demonstrating enzalutamide resistance, thus inducing efficient targeting of these therapy PCa refractory lines. This B7-H3 targeting NK platform demonstrates broad translational potential. GMP production of GTB-5550 has been initiated.
ESMO IO 2021 presentation details
e-Poster Display Title (#126P): Novel B7-H3 targeting dual nanobody NK cell engagers display robust activity against a broad spectrum of solid and hematologic malignancies
The full abstract has been published on ESMO (Free ESMO Whitepaper)-IO website and the Company has published the poster on the company’s website in the "Presentations" section of its corporate website.
For event details please visit: View Source
About Camelid Antibodies
Camelid antibodies are single domain antibodies (sdAbs) from the Camelidae family of mammals that include llamas, camels, and alpacas. These animals produce 2 main types of antibodies. One type of antibody camelids produce is the conventional antibody that is made up of 2 heavy chains and 2 light chains. They also produce another type of antibody that is made up of only 2 heavy chains and no light chain. This is known as heavy chain IgG (hcIgG). While these antibodies do not contain the CH1 region, they retain an antigen binding domain called the VHH region. VHH antibodies, also known as single domain antibodies, contain only the VHH region from the camelid antibody. Camelid antibodies have key characteristics, which include high affinity and specificity (equivalent to conventional antibodies), high thermostability, good solubility and strictly monomeric behavior, small size, relatively low production cost, ease of genetic engineering, format flexibility or modularity, low immunogenicity, and a higher penetration rate into tissues.
About GTB-5550
GTB-5550 TriKE product candidate is being developed for the treatment of B7H3+ solid tumor cancers. GTB-5550 is a single-chain, tri-specific scFv recombinant fusion protein conjugate composed of the variable regions of the heavy and light chains of anti-CD16 and anti-B7H3 antibodies and human IL-15.
About GTB-3650
GTB-3650 is the Company’s lead second-generation Tri-Specific Killer Engager TriKE program currently in preclinical development for the treatment of relapsed/refractory acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS).