DDW Editor Reece Armstrong speaks to Christian Leisner, Chief Executive Officer of antibody therapeutics’ developer CDR-Life about methods to increase access to antigens and improving immunotherapy treatments.
RA: Why are existing immunotherapies restricted to certain patient populations?
CL: Immunotherapies, principally anti-PD-1/-L1 checkpoint inhibitors, have shown therapeutic benefit in improving the prognosis of patients but only in a select handful of solid cancers. This prognostic benefit is mainly restricted to patients who have ‘hot’ tumours which have multiple genetic mutations and are rich in killer T-cells. For patients with ‘cold’ tumours where there is a paucity of killer T-cells, or in ‘hot’ tumours that have become resistant to licensed checkpoint inhibitors, there are currently very few effective therapeutic options available. Bispecific T-cell engagers are modular drug molecules which are specifically developed to kill cancer cells by forming a ‘bridge’ between a target expressed on the surface of cancer cells and killer T-cells.
The arm of the engager which binds killer T-cells (known as a CD3 T-cell binder) is functionally designed to activate T-cells. T-cell activation not only causes the death of cancer cells through the release of special T-cell proteins which punch holes in their surface, but it also triggers the proliferation of killer T-cells at the tumour site (thereby increasing the ‘hotness’ of the tumour). This can potentially amplify additional rounds of cancer cell killing when the patient receives further doses of a T-cell engager.
RA: Could you discuss the major histocompatibility complex (MHC) and how targeting this could bring novel advancements to immunotherapies?
CL: The major histocompatibility complex (MHC) traffics fragments of intracellular proteins known as peptides to the cancer cell surface. This MHC-restricted surface presentation of peptides gives access to a new class of attractive intracellular cancer targets for the potent T-cell engagers which we have developed at CDR-Life.
RA: What kind of cancers could benefit from this treatment approach?
CL: Recent findings from clinical trials evaluating T-cell engagers in mainly ‘cold’ tumours, such as prostate cancer (REGN5678) or small cell lung cancer (Tarlatamab), have shown that ‘cold’ tumours can be made hotter through the activation of T-cells, leading to tumour eradication that meaningfully improves patient prognosis. Following this paradigm, we at CDR-Life believe that the same is achievable in other cancer types, such as non-small cell lung cancer, bladder, squamous head and neck, colorectal, gastric and triple-negative breast cancers, by targeting antigens which are presented as peptides on the surface of cancer cells in an MHC-restricted manner.
RA: Could you discuss the TCR T-cell target MAGE-A4 and what discoveries could be made by targeting this protein?
CL: MAGE-A4 is an intracellular protein that is specifically expressed in cancer cells. MAGE-A4 is known to be highly expressed in several common cancer types including subtypes of non-small cell lung cancer, head & neck, gastric, ovarian and bladder cancers. At CDR-Life, we are developing a highly potent and specific T-cell engager (called CDR404) which uniquely has two binders targeted against a MAGE-A4 peptide presented on MHC with the promise of delivering a highly effective and selective, off-the-shelf, immunotherapy to patients with MAGE-A4 expressing common solid cancers.
RA: What kind of T-cell response can we expect from the MHC-targeting antibody fragment-based approach?
CL: The use of antibody fragments enables us to target MHC-peptides in a far more specific manner than has previously been achieved with earlier antibody approaches, which have been plagued by off-target activity. By adding an affinity-optimised CD3 binding moiety, these bispecific molecules result in a highly tumour-targeted T-cell response that leads to the killing of cancer cells. These antibody fragments are modular, so we can piece them together to create the optimal format that is most potent in terms of cancer cell elimination.
At CDR-Life, we believe that our antibody-based, modular, T-cell engager platform, which is directed against MHC-peptide targets, has excellent drug properties and is potentially superior to the soluble TCR-based T-cell engagers that are currently in clinical development.
RA: In terms of developing antibodies directed against MHC, are there any manufacturing and engineering challenges?
CL: The largest hurdle in this approach is developing molecules that can bind in a very specific manner to the extremely small and difficult-to-access peptides (roughly 10 amino acids) presented by MHC on the surface of cancer cells. To make a target binder that binds only to that specific cancer peptide of interest and not to similar peptides elsewhere in the human body is difficult, and scientists haven’t been able to do this with antibodies in the past.
To overcome this challenge, we at CDR-Life have developed the M-gager platform to leverage the potential of antibody fragments as T-cell engagers. This, we believe, has now opened the door to enable a new class of T-cell engagers to be developed to treat patients in the clinic.
RA: What about side-effects? Is cytokine release something you’re worried about with this approach?
CL: We have engineered a panel of CD3 binders with different binding affinities that have allowed us to generate potent cancer cell killing T-cell engagers with lower cytokine release. In addition, more precise targeting of cancer cells leads to less off-tumour T-cell engagement, which is expected to improve patient safety by reducing the incidence and severity of cytokine release syndrome (CRS), an immunological toxicity which is commonly seen in the clinic as a class effect of T-cell engagers. Overall, our ambition is to create antibody-based T-cell engagers that have high clinical efficacy, can improve patient prognosis, and have a comparably better immunologic safety profile than its competitors.
DDW Volume 24 – Issue 4, Fall 2023
Biography:
Christian Leisner, PhD, Chief Executive Officer of CDR-Life is a seasoned drug developer who has worked in all phases of drug development within both biotech and pharma. He has led global programs with new biologic entities from preclinical through clinical proof of concept within Novartis and has served as part of the senior management team at ESBATech.
