Bispecific antibodies are following hot on the heels of CAR T-cell therapies and paving the way for more accessible and timely treatment for patients with life-limiting diseases such as cancer. Saša Janković finds out more.
Bespoke, personalised blood cancer treatment was revolutionised by the approval of the first chimeric antigen receptor (CAR) T-cell therapy in 2017, and they continue to offer an improved quality of life for many patients.
More recent advancements have taken this to the next level, with off-the-shelf alternatives emerging from the development pipeline. Their name? Bispecific antibodies.
These are next generation monoclonal antibodies (mAbs). While typical mAbs target one epitope, bispecific antibodies have two distinct binding domains that can bind to two antigens or two epitopes of the same antigen simultaneously, causing multiple physiological or anti-tumour responses.
As a result, the treatment may act like a combination of two mAbs, but drug developers need to manufacture only one molecule, and patients may need only one antibody treatment.
And their benefits don’t end there.
Development milestones
Bispecific antibodies have been in development for several decades, and as of August 2023 there were approximately 160 in clinical trials and a further 460 in pre-clinical development.
Over 85% of bispecific antibodies in clinical trials are aimed at cancer therapeutics, but others are focused on chronic inflammatory, autoimmune, and neurodegenerative diseases; vascular, ocular and haematologic disorders; and infections.
‘Bispecific antibody therapies show promise and encouraging outcomes to date,’ says Dr Harriet Walter, associate professor of medical oncology and honorary consultant medical oncologist at the University of Leicester, and a medical advisor at Cancer Research UK.
‘We have seen particular success in haematological indications including non-Hodgkin lymphoma and myeloma, including in the post-transplant and CAR T-cell populations.’
In addition, research into bispecific antibodies has shown other promising results. ‘We are seeing encouraging developments in the treatment of certain solid tumours, with US Food and Drug Administration and European Medicines Agency (EMA) approval of tebentafusp-tebn for HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma’, says Dr Walter.
‘Tarlatamab in the treatment of small cell lung cancer has also shown impressive activity in the relapsed setting, with response rates of 40% and median overall survival of over 14 months in the phase 2 DeLLphi-301 trial, far exceeding historical treatment pathways, [and] the Phase 3 trial is ongoing.’
The list of recent approvals and recommendations for this drug class is extensive and includes:
- June 2022 – Roche’s mosunetuzumab (brand name Lunsumio) approved by the EMA for relapsed or refractory (R/R) follicular lymphoma after two or more prior systemic therapies
- August 2022 – the European Commission (EC) granted conditional marketing authorisation of Janssen’s teclistamab (brand name Tecvayli) as a monotherapy for the treatment of adult patients with R/R multiple myeloma who have received at least three prior therapies
- July 2023 – conditional marketing authorisation in the EU for Genentech’s glofitamab (brand name Columvi) to treat R/R diffuse large B-cell lymphoma (DLBCL)
- August 2023 – the EC granted conditional marketing authorisation for Janssen’s talquetamab (brand name Talvey) as monotherapy for the treatment of adult patients with R/R multiple myeloma
- September 2023 – AbbVie’s epcoritamab (brand name Tepkinly) granted conditional marketing authorisation by the EC as a monotherapy for adult patients with R/R DLBCL after two or more systemic therapies. The Medicines and Healthcare products Regulatory Agency followed suit the following month
- October 2023 – a further development for glofitamab as the NHS announced fast-tracking the treatment following National Institute for Health and Care Excellence (NICE)’s recommendation
- February 2024 – NICE recommends epcoritamab for DLBCL after two or more lines of treatment.
Also on the horizon is Regeneron’s odronextamab, which is currently entering Phase 2 and 3 trials for R/R follicular lymphoma; and Amgen’s small cell lung cancer treatment tarlatamab – a bispecific T-cell engager class of artificial bispecific monoclonal antibodies that are being investigated for use as anti-cancer drugs.
CAR T versus bispecific antibodies
A clinician’s choice of CAR T-cell therapy versus bispecific antibodies depends on the characteristics of the disease being treated and the treatment’s approved indications, as well as the health of the patient.
CAR T-cell immunotherapy involves the extraction of T-cells from the patient, genetic modification of these cells in a laboratory setting to express the CAR, and then reinfusion of the engineered T-cells back into the patient to seek out and eliminate cells expressing the target antigen.
CAR T-cell product is given on a one-time basis, usually involving the patient travelling to a CAR T-cell therapy centre and remaining there for around a month due to the time required to manufacture the T-cells.
Dr David Tucker, substantive consultant haematologist leading the haematology Clinical Trials Unit at the Royal Cornwall Hospital, who is also the regional lead for non-malignant haematology research for the National Institute for Health Research (NIHR) clinical research network, has conducted seven clinical trials on bispecifics.
He says, in his practice, ‘CAR T therapy has a delay because patients have to have T-cells removed and sent to US where they are bio engineered before being returned to the patient, which can take three to six weeks’.
For a patient who needs treatment quickly, this may not be a viable option.
Another drawback to CAR T-cell therapy is that the sites that administer CAR T tend to be in bigger cities, ‘so for patients in far-flung places, or who are older and ill with cancer, travelling is no mean feat’, Dr Tucker adds.
A timely and accessible option
The off-the-shelf nature of bispecific antibodies means they can offer a timelier and more accessible alternative. They are administered as drugs, typically through intravenous infusion, as ongoing treatment often needing to be administered over a period of a year or more.
‘Bispecific antibodies are readily available, readily accessible, and NICE-approved in the UK to be used in district general hospitals across the country in haemato-oncology units. [They are] administered by the same nurses who would normally give chemotherapy’, Dr Tucker says.
Dr William Townsend, consultant haematologist at University College Hospital London and an advisor to the charity Lymphoma Action, says, bispecific antibodies could ‘potentially benefit more patients than CAR T-cell therapy because they enable treatment to be started sooner, and at locations that are more convenient for patients’.
What’s more, from a patient perspective, Dr Walter says: ‘Hospitalisation requirements and lower risk of severe cytokine release syndrome and neurological toxicity with bispecific therapies also confer potential benefits.’
And another perceived benefit is ‘the flexibility to potentially combine different bispecific constructs and target multiple-target tumour antigens and effector cells’, as well as ‘the ability to interrupt dosing if required due to toxicity’, she adds.
Research is also looking at how to harness the potential of bispecific antibodies in combination with other chemo-immunotherapeutic approaches to target unmet needs.
‘Despite ongoing waves of innovation in oncology, there remain significant unmet medical needs for patients’, says Edmond Chan, senior director, Europe, Middle East and Africa (EMEA) therapeutic area lead, haemato-oncology at Janssen EMEA. ‘For example, multiple myeloma remains incurable and with each line of additional therapy, patients face shorter remissions and more frequent relapses.
‘Another example is lung cancer, which is Europe’s biggest cancer killer, causing more deaths than breast cancer and prostate cancer combined. Of all lung cancers, non-small cell lung cancer accounts for around 85% of cases, where patients often face poor outcomes as they become resistant to standard treatments.’
While bispecific antibodies might not be suitable for everyone, healthcare professionals having another potential option in the treatment arsenal is certainly advantageous.
Current challenges and research opportunities
While their benefits cannot be ignored, there remain some unavoidable – for now – downsides to bispecific antibodies, including the obvious point of not yet having long-term data.
‘Although bispecifics are a very exciting development I don’t think at the moment they’re in a place to replace CAR T-cell therapy because we don’t yet have data that shows they have a curative effect, and we also don’t have long-term data on survival,’ says Dr Tucker.
‘At the moment I wouldn’t say that they were a substitute, but they can be a useful alternative for patients who are perhaps a bit frail or are unable or unable to travel or receive CAR T-cell therapy for some other reasons.’
Dr Walter adds that one of the major challenges is understanding how best to sequence bispecific antibodies with other approaches, including CAR T-cell therapies, particularly in haematological indications where both are approved.
She says working out ‘who benefits most from which approach and at what point in their disease trajectory’ is particularly important where both approaches are directed against the same tumour antigen, since ‘we know that antigen escape is one mechanism of resistance that can occur’.
‘Other potential barriers lie in the risks associated with stimulation of the immune system, which we also need for these agents to work’, Dr Walter continues.
‘However, with increasing knowledge of the toxicity profiles, mitigation strategies, such as step-up dosing and pre-treatment with steroids, this risk is significantly reduced.’
There are also perceived barriers to the success of bispecific antibodies in solid tumours.
Dr Walter says these are around ‘identification of suitable target antigens, avoiding the inevitable adverse effects on normal tissues, and potential limited access of bispecifics to the tumour site due to disordered neovasculature and stromal tissue as well as “cold” tumours’.
However, she adds that ‘approaches using, for example, T-cell stimulating vaccines are currently being explored’.
Raising awareness of bispecific antibodies
Despite increasing access, the awareness of, and confidence in, bispecific antibody treatment on the part of patients and healthcare professionals remains an additional hurdle to its adoption.
‘The challenge we face now is gathering experience and empowering doctors in district general hospitals who wouldn’t have experienced bispecific antibodies to have the confidence to use them’, says Dr Tucker. ‘We need to give them some education and training and reassurance that it’s safe to do so.’
Involving the patient and their families at every step of the process and ensuring they fully understand their treatment is also imperative.
‘We bring the patient along very closely – for example with regular meetings with the myeloma patient associations in Europe – to work out what we can help them to build for the patient so they will better understand the benefits and risks of these new therapies and how it is going to change their life,’ says Dr Chan.
‘We also work with European patient associations in the development stage of clinical trials to make sure that we are explaining things properly to the patients – including things like consent forms – to ensure that we are doing everything we can to make sure that patients are well looked after.’
Future trajectory
All things considered, experts agree that the future looks bright for bispecific antibodies – as well as for the patients who will benefit from them.
Dr Walter says the high response rates seen with bispecific therapies, and increasing long term safety and efficacy data, means ‘we are now seeing these agents being incorporated earlier in the treatment paradigms with the aim of improving outcomes earlier in the treatment pathway [and] we also assume these treatments work best in the setting whereby effector cells are least likely to be deleted or exist in an “exhausted state”.’
Dr Tucker agrees, saying: ‘I think once bispecific antibodies get fully licensed and approved, we will see them in widespread use at least after second line treatment, and moved up the sequence for use either in combination with first line chemotherapy, or second line chemotherapy, or even using them in on their own or with a novel agent like lenalidomide. They might even end up replacing the monoclonal antibodies such as rituximab or obinutuzumab.’
He adds: ‘We don’t yet know where they’re going, where is the right place to use them, or whether you can use them more than once. But they’re showing such efficacy that I think they may well change our frontline management of high grade and low-grade lymphoma if they appear to be well tolerated and effective.
‘I think they will be the most impactful treatment change since CAR T-cell therapy was approved.’
Undoubtedly, much more research, development and clinical applications of bispecific antibodies can be expected.
The FDA is already talking up what it calls ‘a dizzying array’ of potential formats for multispecific antibodies, which can target multiple antigens simultaneously and, it says, ‘may lead to treatments for diseases with no or few therapies’.
‘With expanding indications and increased knowledge of how best to use these antibodies, as well as new combination approaches, there is much still to learn and I think we see this landscape evolve over the next few years’, concludes Dr Walter. Watch this space.
