OBJECTIVES
With PB001, Pure Biologics aims to develop a recombinant bispecific monoclonal antibody as a therapeutic candidate for use in immunotherapy of colorectal cancer. The antibody will simultaneously target cytotoxic lymphocytes and also a tumor cell surface antigen. Key aspects of the project include the selected targets and their differential expression in a tumor disease state. This highlights a novel and previously unexplored mechanism of action, via simultaneous engagement and activation of cytotoxic lymphocytes.
DESCRIPTION
Therapies focusing on immune checkpoint inhibition offer attractive targets for novel drug development. Our Company has identified two promising targets, one which is overexpressed in colorectal cancer, with limited expression in healthy cells, and another found in a subpopulation of T lymphocytes – immune defense cells. The goal of our intended drug molecule will be to activate immune cells which are otherwise not effectively engaged in fighting the tumor.
To elicit an immune response against the cancer, two conditions must be met: recognition of tumor cells by T lymphocytes, and activation of those lymphocytes. Various receptors and ligands regulate pathways through which T lymphocytes are engaged, either through their stimulation and/or their inhibition. These molecules are known as immune checkpoints and their regulation is one of the most promising future therapies.
We hypothesize that our new first-in-class bispecific antibody will synergistically drive a bridging, or engagement of factors, that:
– reverse T-cell exhaustion and activate lymphocytes in the tumor microenvironment,
– direct leukocytes (lymphoid or myeloid) to attack tumor cells.
To test these hypotheses, a series of in vitro experiments will be performed to characterize the biological mechanisms of action in cell culture.
Upon successfully demonstrating efficacy using in vitro test systems, in vivo studies will be performed that examine toxicological profiles, therapeutic doses and efficacy of bispecific antibodies in humanized mice expressing the selected targets. Looking ahead, the drug candidate is then expected to enter a first-in-human clinical trial in patients.
PROJECT PROGRESS
Project closed. In 2023, work continued on the previously identified unique anti-TIM3 antibody in the PB001 project, as well as on the validation of the advantages of the bispecific TIM3xTAA format in vivo.
A study on a human tumour model in humanised mice was conducted in June 2023 in collaboration with GemPharmatech (China). The aim was to validate the TIM3xTAA therapeutic format by comparing its anti-tumour activity with that of the anti-TIM3 monoclonal antibody, as well as to validate the activity of the unique PB001.TM14 antibody obtained in relation to the reference anti-TIM3 molecules currently in clinical development: Sabatolimab (Novartis) and Sym023 (Symphogen).
The study did not demonstrate the superiority of the bispecific TIM3xTAA format over monospecific anti-TIM3 antibodies in terms of therapeutic efficacy, meaning that proof of concept for the PB001 project was not achieved. This result, together with earlier failures in the selection of anti-TAA antibodies, which were to be a critical component of the bispecific antibody, made it necessary to discontinue work on the bispecific molecule. Nevertheless, the results obtained for the PB001.TM14 antibody were comparable to those of reference molecules (Sabatolimab, Sym023), confirming the previously obtained in vitro results. The preliminary safety profile of the test molecule was also comparable to that of antibodies currently being tested in clinical trials, which is a satisfactory result from the perspective of further development of the drug candidate. In addition, an additional control group was included in the study to preliminarily evaluate the combination therapy of anti-TIM3 with chemotherapy, and thus evaluate a potentially new therapeutic concept using the discovered antibody. A full analysis of the results will allow for the formulation of final conclusions from the in vivo study and a decision on the further development of the PB001.TM14 antibody.
An analysis of the project’s viability conducted in the third quarter of 2023 showed that the TIM3xTAA format lacked therapeutic potential and, consequently, that the basic objectives of the PB001 project could not be achieved within the eligibility period for funds granted by the National Centre for Research and Development (NCBR). As a result, the Company decided to discontinue the development of the bispecific TIM3xTAA antibody and subsequently submitted a final report to the NCBR. The project was closed after the report was approved.
The result of the project is a unique anti-TIM3 antibody, PB001.TM14, with anti-tumour properties comparable to those of competing antibodies, to which the Company holds full rights. In addition, the PB001.TM14 antibody has the potential for further therapeutic development as a monoclonal antibody for combination therapy with PD1 receptor blockers.
Due to the closure of the project, the Company does not plan to continue research work under project PB001. Currently, the possibility of commercialising the know-how and assets developed during project PB001 is being analysed, and the validity of a patent application for the PB001.TM14 antibody is being assessed.
PROJECT DATA SHEET
Title: Development of the bispecific antibody for the immunotherapy
Program: Smart Growth Operational Programme 2014-2020
Project number: POIR.01.01.01-00-0947/17
Value: PLN 13 709 140,77
Contribution of European Funds: PLN 10 967 312,61
Start: February 1, 2018
End: September 29, 2023
