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Review

Current Indications and Future Landscape of Bispecific Antibodies for the Treatment of Lung Cancer

by
Hugo Arasanz
1,2,†,
Luisa Chocarro
3,†,
Leticia Fernández-Rubio
3,
Ester Blanco
3,4,
Ana Bocanegra
3,
Miriam Echaide
3,
Ibone Labiano
2,
Ana Elsa Huerta
2,
Maria Alsina
1,2,
Ruth Vera
1,2,
David Escors
3 and
Grazyna Kochan
3,*
1
Medical Oncology Department, Hospital Universitario de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain
2
Oncobiona Group, Navarrabiomed, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain
3
Oncoimmunology Group, Navarrabiomed, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain
4
Division of Gene Therapy and Regulation of Gene Expression, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(12), 9855; https://doi.org/10.3390/ijms24129855
Submission received: 17 February 2023 / Revised: 2 June 2023 / Accepted: 5 June 2023 / Published: 7 June 2023
(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain 2.0)
Browse Figures
Review Reports Versions Notes

Abstract

:
Bispecific antibodies are a promising type of therapy for the treatment of cancer due to their ability to simultaneously inhibit different proteins playing a role in cancer progression. The development in lung cancer has been singularly intense because of the increasingly vast knowledge of the underlying molecular routes, in particular, in oncogene-driven tumors. In this review, we present the current landscape of bispecific antibodies for the treatment of lung cancer and discuss potential scenarios where the role of these therapeutics might expand in the near future.

1. Introduction

Nowadays, numerous antibody-based proteins are being preclinically and clinically developed and have proven to be useful research, diagnosis, and therapy tools due to their particular properties, such as high specificity and affinity [1]. However, their large molecular weight (~150 kDa) and their challenging high-cost production limit their capacities. Thus, other novel strategies, such as nanobodies and bispecific antibodies, are being developed to overcome those limitations and improve their pharmacological properties and efficacy [2,3].
Classical antibodies or immunoglobulins are formed by two identical heavy and two identical light chains connected with disulfide bonds representing a Y-shaped molecule [4]. The heavy chain comprises four domains, and the light chain folds into two domains [5]. At the end of each chain is the antigen-binding fragment, which corresponds to the variable region of the antibody [1,4].
During the early 1990s, Hamers-Casterman and her team discovered a new type of antibody circulating in Camelidae (including camels and llamas) devoid of light chains that are called “heavy chain-only antibodies” [6]. Their heavy chain structure consists of two constant regions, a hinge region and the antigen-binding domain (VHH) [1]. The VHH is the structural and functional equivalent of the antigen-binding fragment of conventional antibodies [5]. It is also referred to as a nanobody or single-domain antibody and is considered to be the smallest antigen-binding unit of an antibody. Its small molecular size (~15 kDa) allows it to penetrate easily into tissues, cross the blood–brain barrier, and invade solid tumors [7,8]. In addition to their small size, other unique advantages, such as their remarkable stability against extreme temperatures, high pressure, chemical denaturants, low pH, or the presence of proteases, make nanobodies an attractive option over conventional antibodies [1,3,7,9]. Hence, nanobodies share characteristics of small molecule drugs and monoclonal antibodies, and they may be a promising alternative to classical antibodies in some applications [1]. Currently, many nanobody-based strategies are being developed for cancer, molecular imaging, infectious diseases, or inflammatory conditions, among other medical fields [3].
On the other hand, bispecific antibodies are molecules composed of one core unit and two binding units that are specific to two different epitopes, thus being able to attach to two targets simultaneously. The clinical applications of these antibodies are numerous, and they might be particularly useful in cancer because of the great complexity of this disease, with intertwined oncogenic signaling routes able to bypass single target inhibition upstream. Moreover, several clinical trials have demonstrated greater efficacy when patients receive combined targeted therapies, including CTLA4 plus PD-1-blocking antibodies or BRAF- and MEK-targeted antibodies, strongly supporting the potential benefit of this strategy [10,11,12,13,14,15].
Bispecific antibody development strategies can be bifurcated into two categories, the antigen x antigen type and the antigen x cell-engager type. Additionally, from the perspective of molecular format, bispecific antibodies can be classified into the “full antibody type” and the “BiTE type” (Figure 1). Depending on the molecular format, different development strategies should be required. For instance, the antigen x antigen bispecific type simultaneously targets two tumor-expressed antigens (TAAs), generally inhibiting two cancer signaling pathways to inhibit tumor growth. Of note, a particular subtype of bispecific antibodies has been named after the acronym BiTE (Bispecific T-cell engager). They are small molecules consisting of two fused scFvs without Fc region; one of them targets a (TAA), and the other one is specific to a T cell-surface receptor, generally CD3, one of the components of the T cell receptor (TCR). When a BiTE engages CD3 and the tumor-associated antigen, it induces T cell activation and proliferation while, at the same time, ensuring the immunological synapse [16] and enhancing T cell cytotoxicity for the recognition and elimination of tumor cells. Currently, several BiTEs are being developed for the treatment of cancer, the one targeting DLL3 and CD3 being the most promising one for the treatment of lung cancer, demonstrating enhanced T-cell cytotoxicity against DDL3+ tumor cells (NCT05882058).

2. Approvals in Oncology

In 2009, the first bispecific antibody, catumaxomab, was approved in the European Union as an intraperitoneal therapy for malignant ascites. Unfortunately, it was found to be toxic because of Fc-mediated off-target T-cell activation in the liver and was voluntarily withdrawn from the market.
Further on, blinatumomab (Blincyto), a bispecific CD19-directed CD3 T-cell engager, received accelerated approval by the FDA in December 2014 and by the EMA in 2015 for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia (ALL). Regular approval was obtained in July 2017 after the results of the phase III trial TOWER (NCT02013167), finding a benefit in overall survival (7.7 vs. 4.0 months, HR 0.71, p = 0.01) and event-free survival (6-months 31% vs. 12%, p < 0.001) compared with standard chemotherapy in patients with B-cell precursor ALL that had progressed to at least one line of therapy [17].
During the last few years, other bispecific antibodies have been approved for the treatment of hematological malignancies. BCMA-targeted therapies have proven to be effective in patients with multiple myeloma. Belantamab mafodotin (Blenrep) was the first one to receive authorization for its use in August 2020, shortly followed by teclistamab (Tecvayli), with a breakthrough designation in 2022 by the FDA and also approved by the EMA the same year based on the results of the phase Ib trial MajesTEC-1. Moreover, in patients with multiple myeloma, talquetamab, a bispecific antibody targeting GPRC5D and CD3, was named a breakthrough therapy after the results of phase I MonumenTAL-1.
For the treatment of relapsed follicular lymphoma, the anti-CD20/CD3 antibody mosunetuzumab (Lunsumio) was approved in June 2022 by the EMA as a therapy after progression to two previous lines of treatment. A single-arm phase II trial found a complete response rate of 60%, much higher than the 14% obtained with copanlisib in previous trials [18].
To conclude, bispecific antibodies have also proven effective for the treatment of solid tumors, and two drugs for the treatment of neoplasms other than lung cancer have been approved in 2022. Tebentafusp (Kimmtrak), targeting gp100, was approved by the FDA and EMA for the treatment of uveal melanoma with HLA-A*02:01. Phase III IMCgp100-202 compared tebentafusp with the therapy chosen by the investigator (pembrolizumab/ipilimumab/dacarbazine), and found a benefit in progression-free survival (31% vs. 19% at 6 months, p = 0.01) and overall survival (83% vs. 59% at 1 year). Lastly, cadonilimab (anti-PD1/CTLA4) was approved in China in June 2022 for patients with relapsed or metastatic cervical cancer after progression to platinum-based chemotherapy [19]. Even though a phase III trial is still ongoing, the approval was granted based on the promising results of a single-arm phase II with patients that had progressed to one or two lines of treatment, obtaining an overall response rate (ORR) of 33%, median progression free survival (mPFS) of 3.75 months and, more interestingly, median overall survival (mOS) of 17.51 months [20].

3. Bispecific Antibodies for the Treatment of Lung Cancer

Currently, 274 clinical trials are studying bispecific- or nanobody-based strategies for the treatment of solid tumors. Lung cancer patients meet the inclusion criteria in 158 of those clinical trials (Table 1), 5 in early phase I, 91 in phase I, 43 in phase I/II, 12 in phase II, 1 in phase I/II, 1 in phase III, and 4 is not applicable (Figure 2). A brief description of each bispecific antibody is available (Supplementary Materials).
All of them are open-label (no masking), except for one phase II trial (NCT03501056), having quadruple masking (participant, care provider, investigator, and outcomes). Furthermore, many of those clinical trials specifically target lung cancers, such as NCT05116007 and NCT03319940, for small-cell lung cancer (SCLC) or NCT05360381 and NCT02609776 for non-small-cell lung cancer (NSCLC), for example. Many targets are being studied (Figure 2b).
In addition, a couple of diagnostic PET imaging clinical trials are being developed. NCT05156515 and NCT05436093 trials evaluate a non-invasive PD-L1 (APN09 drug) and CLDN18.2 (18F-FDG drug), targeting nanobodies labeled with PET radio-nuclide as a molecular imaging tracer for PET/CT scan, where 68Ga-THP-APN09 PET/CT and 18F-FDG PET/CT diagnostic approaches will be used to detect PD-L1 or CLDN18.2 tumor expression, with the aim of identifying patients who could benefit from anti-PD-L1 or anti-CLDN18.2 therapy. Both are being developed by Peking University Cancer Hospital and Institute.

3.1. Non-Small-Cell Lung Cancer

NSCLC is one of the tumor types with the higher incidence worldwide. It is usually classified into two groups, squamous and non-squamous. The greater knowledge of the mutational landscape that drives tumor progression in NSCLC allowed a further division based on gene mutation, particularly in non-squamous tumors. In this context, different targeted therapies have been developed, having demonstrated a higher efficacy with a more favorable toxicity profile compared with conventional treatments.
At this moment, amivantamab-vmjw is the only bispecific antibody available for the treatment of lung cancer. It is a human IgG1-based antibody that targets EGFR and MET, and it also induces Fc-dependent trogocytosis (an active transfer of a fraction of a cell to another, including the membrane and/or surface molecules) by macrophages and antibody-dependent cytotoxicity (ADCC) by natural killer (NK) cells [21]. It was granted accelerated approval by the Federal Drug Agency (FDA) in May 2021 and was approved by the European Medicines Agency (EMA) that same year for patients with NSCLC and EGFR ex20ins mutations that have progressed to platinum-based chemotherapy. Approval was granted on the basis of the results of the phase I CHRYSALIS, which included 81 patients, and reported an ORR of 40% and median duration of response (mDOR) of 11.1 months. The most frequent adverse events were rash (86%) and paronychia (45%), but no G3-4 toxicities surpassed 5%, hypokalemia (5%), rash (4%), PE (4%), diarrhea (4%) and neutropenia (4%) being the most common [22].
Some combinations of amivantamab with other drugs are also in the advanced stages of development. Phase II CHRYSALIS-2, evaluating the combination of amivantamab with the third generation EGFR TKI inhibitor lazertinib in patients with EGFR mutant NSCLC after progression to osimertinib and platinum-based chemotherapy, was presented in ASCO Congress 2022, describing an ORR of 33% with mDOR of 9.6 months, irrespective of the original mutation or the sequence of treatment. Toxicity was comparable with the one reported in the CHRYSALIS trial [23]. A confirmatory phase III trial called MARIPOSA-2 (NCT04988295), comparing chemotherapy plus amivantanab and Llzertinib with chemotherapy in patients that have progressed to osimertinib, is enrolling patients at this moment. Moreover, phase III trial MARIPOSA (NCT04487080), which will compare this combination with osimertinib or lazertinib monotherapy as a frontline treatment, is currently ongoing [24]. Finally, phase III trial PAPILLON (NCT04538664) is evaluating the benefit of the addition of amivantamab to platinum-based chemotherapy in patients with NSCLC and EGFR exon 20 insertions, and preliminary results are expected to be published within the next few years.
To conclude, zenocutuzumab, an HER2 and HER2 bispecific antibody, is also under evaluation, with a special focus on patients with NRG1 fusion. NRG1 is a membrane glycoprotein involved in cell growth and differentiation, which acts as a ligand for ERBB3 and ERBB4. Under common circumstances, NRG1 is cleaved by proteases and released in its mature form, limiting its activity. However, NRG1 fusions are poorly attached to proteases, favoring the accumulation of the protein in the membrane and its binding to HER3, causing heterodimerization with HER2 and downstream signal transduction. The combined results of the phase II part of the basket trial and the early expanded access program revealed an ORR of 34% among the 41 patients with NSCLC, with an mDOR of 9.1 months for the whole cohort, and less than 5% of G3 adverse events.

3.2. Small-Cell Lung Cancer

SCLC is a neoplasm of neuroendocrine origin strongly associated with a smoking habit. It is characterized by a poor prognosis, with cancer cells presenting a very high proliferative rate and early metastatization. The high cellular heterogeneity, with a high mutation burden, is a major barrier to the incorporation of new treatments into the therapeutic arsenal, as targets expressed by all the cells are uncommon. From a molecular point of view, the inactivation of tumor suppressor genes defines this disease, with TP53 and RB1 being dysfunctional in most cases.
In recent years, immunotherapy has been positioned in the frontline treatment of small-cell lung cancer, and at this very moment, two immune-checkpoint inhibitors, atezolizumab and durvalumab, are widely used combined with chemotherapy [25,26]. However, the efficacy is modest, probably due to the great cell plasticity and tumor heterogeneity, and new treatment strategies combining different approaches might be advantageous.
Delta-like ligand 3 (DLL3) is an inhibitory ligand of the NOTCH pathway frequently upregulated in SCLC that promotes cell invasion and metastases through epithelial-to-mesenchymal transition (EMT) [27]. Several early trials evaluating the efficacy of tarlatamab, a novel DLL3-targeted BiTE, in patients with SCLC, have reported appealing outcomes. In ASCO Annual Meeting 2021, the results of the phase I trial DeLLphi-300, in which patients with SCLC were treated with tarlatamab after progression to platinum-based chemotherapy, were presented. Even though 40% had previously received immune-checkpoint inhibitors (ICI) and 47% had liver metastases, usually associated with resistance to ICI, ORR was 20% with mDOR of 8.7 months, and disease control was achieved in 47%. The drug’s toxicity was manageable; 27% presented G3 treatment-related adverse events (TRAEs), which forced the interruption of the treatment in 7.6% of patients; additionally, 44% of patients experienced cytokine-release syndrome (CRS) [28]. The final results were recently published, reporting an ORR of 23.4% with an mDOR of 12.3 months, an mPFS of 3.7 months, and a mOS of 13.2 months. Tumor DLL3 expression was associated with better outcomes. The main TRAEs were CRS (52.3%), pyrexia (40.2%), constipation (30.8%), and 30.8% experienced toxicity ≥ G3 [29].

3.3. Toxicity of Bispecific Antibodies

Up to date, TRAEs caused by bispecific antibodies being evaluated for the treatment of lung cancer appear manageable, although the very structure of the BiTE tarlatamab and its immune-stimulating effect confers a less favorable toxicity profile compared with zenocutuzumab and amivantamab.
Patients treated with tarlatamab experience G3-5 TRAEs more frequently than those receiving zenocutuzumab or amivantamab, with CRS and neurological adverse events (AEs) being particularly concerning. Moreover, it should be taken into account that most oncologists treating lung cancer might not have any previous experience in the management of either CRS or immune effector cell-associated neurotoxicity syndrome (ICANS), so an additional effort to ensure proper handling would be of great interest [29].
Regarding zenocutuzumab and amivantamab, besides the aforementioned TRAEs, infusion reactions were frequent, as high as 66% in patients receiving the latter [22]. Tight surveillance and patient education might be useful to adequately manage these episodes.

4. Future Areas of Development

Some clinical scenarios might be of greater interest for the use of bispecific antibodies. Particularly in patients with mutation-driven NSCLC, both concurrent de novo gene alterations and their emergence as resistance mechanisms to targeted therapies are common. In patients with EGFR mutant NSCLC, concomitant MET, HER2, and PI3KCA alterations are the most frequent, reaching up to 19%, 5%, and 7% after progression to osimertinib, respectively. This is the rationale underlying the clinical trials with the EGFR/MET bispecific antibody amivantamab, but other drugs could also be evaluated in this context [30].
Regarding other oncogene-driven NSCLC, comparable resistance mechanisms can be found, although in different proportions. After progression to ALK-targeted therapies, common off-target mutations include EGFR alterations, HGF/MET pathway activation, and KIT amplification, among others [31]. Off-target mechanisms were detected in 45% of NSCLC patients with MET ex14 mutations after treatment with TKIs [32,33]. Alterations in different points of the RTK/RAS/MAPK/PI3K pathway were observed in 5 out of 10 patients with NSCLC and KRAS G12C mutation treated with adagrasib [34]. Moreover, RAS, MET, and BRAF were common targetable resistance mechanisms in patients with NSCLC and RET fusion treated with RET inhibitors [35,36].
Concerning immunotherapy treatment, a vast number of different immune checkpoints that play a role in the antitumor immune response suggest that combined blockade might derive greater efficacy. In fact, several trials evaluating the combination of drugs targeting different immune checkpoints in patients with NSCLC have been published. Anti-PD-1 plus anti-CTLA-4 schemes have reported better outcomes [26,37,38], although combinations, including anti-TIGIT or anti-LAG3, among others, are also being explored [39,40].
Of course, this also suggests that bispecific antibodies targeting several immune checkpoints could provide an advantageous strategy and improve efficacy in the treatment of cancer. MEDI5752 is a PD-1/CTLA-4 bispecific checkpoint inhibitor that has been evaluated in patients with different solid tumors. In ESMO Congress 2022 were reported the results of the phase I/II trial in patients with non-squamous NSCLC who received MEDI5752 combined with platinum and pemetrexed. The outcomes were promising, and in a small randomized cohort controlled with placebo, the efficacy was numerically higher in terms of ORR (50% vs. 47.6%, and the difference grew to 55.6% vs. 30% in PD-L1 negative tumors), mPFS (15.1 vs. 8.9 months), and mOS (non-reached vs. 16.5 months). However, due to high rates of toxicity, with 70% G3 adverse events, which led to discontinuation in 70%, a lower MEDI5752 dose of 750 mg instead of 1500 mg is under evaluation [41].
During the following years, the results of ongoing clinical trials are expected to confirm the efficacy of bispecific antibodies. A deeper knowledge of potential targets playing a capital role in tumorigenesis, immune system evasion, or resistance to treatment might entail a great impact on the development and usefulness of these promising therapies.

5. Conclusions

Even though the role of bispecific antibodies for the treatment of lung cancer has been limited to date, the deeper knowledge of the multiple genomic alterations driving tumor progression and treatment resistance suggests that the indications might experience a great expansion during the following years. The progression of mutation-driven tumors is caused by the persistent activation of a protein inducing uncontrolled cell proliferation and tumor growth. Current scientific guidelines recommend the screening of genetic alterations in several genes, including ALK, BRAF V600, EGFR, HER2, KRAS G12C, MET, NTRK1-3, RET, and ROS1 in patients with NSCLC, as drugs targeting these proteins have demonstrated unprecedented efficacy. Concurrent mutations of other oncogenic genes are common, and the simultaneous blockade might be beneficial. Moreover, the treatment with tyrosine kinase inhibitors frequently induces off-target resistance mechanisms that require combined inhibition to prevent further tumor progression. With respect to immunotherapy, although the PD-1/PD-L1 axis has proven to be of utmost relevance, other immune checkpoints play major roles in the immune escape, as demonstrated by several clinical trials [42,43]). A single molecule able to inhibit several of these targets would reduce the complexity of patient management and follow-up. We expect Amivantamab-vmjw to be only the first in this group of drugs with the potential to significantly improve cancer treatment efficacy.

Supplementary Materials

The supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms24129855/s1.

Author Contributions

Conceptualization, H.A. and L.C.; bibliography review, H.A., L.C., L.F.-R., E.B., A.B., M.E., I.L. and A.E.H.; writing—original draft preparation, H.A., L.C. and L.F.-R.; writing—review and editing, H.A., L.C., L.F.-R., E.B., A.B., M.E., I.L., A.E.H., M.A., R.V., D.E. and G.K.; supervision, M.A., R.V., D.E. and G.K. All authors have read and agreed to the published version of the manuscript.

Funding

D.E. is funded by a Miguel Servet Fellowship (ISC III, CP12/03114, Spain). H.A. is supported by the Clínico Junior 2019 scholarship from the AECC (CLJUN19010ARAS). I.L. is financed by National Agency of Research (AEI) in the “Juan de la Cierva-Postdoctoral formación” (8FJC2021-046521-I). L.C. is financed by Instituto de Salud Carlos III (ISCIII), co-financed by FEDER funds, “Contratos PFIS: contratos predoctorales de formación en investigación en salud” (FI21/00080). M.A. is partially financed by the Government of Navarra in the La Caixa Program.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All the data used for this review is presented in the text.

Conflicts of Interest

H.A. has received honoraria for advisory roles from Astra Zeneca and for clinical trial coordination from Ferrer Farma. M.A. has been involved as a consultant for advisory roles with Amgen, BMS, MSD, Lilly, and Servier. M.M. has received honoraria for advisory roles from Pfizer, Boehringer Ingelheim. R.V. has received honoraria for advisory roles and for speaking from Amgen, Bayer, Astra Zeneca, Merck, Roche, Sanofi, MSD, Lilly, Servier, and for consultant roles from Novartis.

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Ijms 24 09855 g001 550
Figure 1. (A) Schematic representation of a conventional human antibody. Heavy chain is represented in blue, light chain is represented in orange. CH: Constant domain of heavy chain. CL: Constant domain of light chain. VH: Variable domain of heavy chain. VL: Variable domain of light chain. (B) Schematic representation of a nanobody. VHH: Single variable domain on a heavy chain. (C) Schematic representation of one modality of a bispecific antibody. The heavy and light chain specific for antigen 1 are represented in blue and orange, respectively. The heavy and light chain specific for antigen 2 are represented in green and yellow. (D) Schematic representation of a Bispecific T-cell Engager (BiTE).
Figure 1. (A) Schematic representation of a conventional human antibody. Heavy chain is represented in blue, light chain is represented in orange. CH: Constant domain of heavy chain. CL: Constant domain of light chain. VH: Variable domain of heavy chain. VL: Variable domain of light chain. (B) Schematic representation of a nanobody. VHH: Single variable domain on a heavy chain. (C) Schematic representation of one modality of a bispecific antibody. The heavy and light chain specific for antigen 1 are represented in blue and orange, respectively. The heavy and light chain specific for antigen 2 are represented in green and yellow. (D) Schematic representation of a Bispecific T-cell Engager (BiTE).
Ijms 24 09855 g001
Ijms 24 09855 g002 550
Figure 2. Clinical landscape of bispecific antibodies for the treatment of lung cancer. (A) Pie charts representing the proportions of clinical trials evaluating bispecific drugs for the treatment of lung cancer, according to the indicated categories. (B) Bar graph representing the number of clinical trials with bispecific antibodies for the treatment of lung cancer targeting the indicated antigens.
Figure 2. Clinical landscape of bispecific antibodies for the treatment of lung cancer. (A) Pie charts representing the proportions of clinical trials evaluating bispecific drugs for the treatment of lung cancer, according to the indicated categories. (B) Bar graph representing the number of clinical trials with bispecific antibodies for the treatment of lung cancer targeting the indicated antigens.
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Table
Table 1. Clinical trials evaluating bispecific antibodies in patients with lung cancer.
Table 1. Clinical trials evaluating bispecific antibodies in patients with lung cancer.
TargetNCT NumberPhaseTreatment
4-1BB/CLDN18.2NCT04900818Phase 1TJ033721
B7-H3/CD28NCT05585034Phase 1XmAb®808
CD3NCT04076137Phase 1T-cell armed with bispecific antibody
CD3/EGFRNCT01081808Phase 1T cells armed with EGFR-bispecific
CD3/HER2NCT02829372Phase 1CD3/HER2 bispecific antibody
CD3/HER2NCT04501770Phase 1M802
CD3/RORINCT05607498Phase 1EMB07
CD39/TGF-βNCT05381935Phase 1ES014
CEA/CD3NCT02324257Phase 1RO6958688
Claudin-2/PD-L1NCT04856150Phase 1Q-1802
CTLA-4/LAG-3NCT03849469Phase 1XmAb®22841
CTLA-4/OX-40NCT03782467Phase 1ATOR-1015
DLL3/CD3NCT03319940Phase 1AMG 757
DLL3/CD3NCT05461287Phase 1QLS31904
DLL3/CD47NCT05652686Phase 1PT217
DLL4/VEGFNCT02298387Phase 1OMP-305B83
DLL4/VEGFNCT03292783Phase 1NOV1501 (ABL001)
DLL3/CD3NCT05361395Phase 1Tarlatamab
EGFRNCT02687386Phase 1Mitoxantrone packaged EDV
EGFRNCT02369198Phase 1TargomiRs
EGFR/4-1BBNCT05442996Phase 1HLX35
EGFR/4-1BBNCT05360381Phase 1HLX35
EGFR/4-1BBNCT05150457Phase 1BNA035
EGFR/cMetNCT04606381Phase 1Amivantamab
EGFR/cMetNCT02609776Phase 1Amivantamab
EGFR/cMetNCT04077463Phase 1Amivantamab
EGFR/CD3NCT05387265Phase 1CX-904
EGFR/HER3NCT04603287Phase 1SI-B001
EGFR/LGR5NCT03526835Phase 1MCLA-158
EGFR/cMetNCT02221882Phase 1LY3164530
EGFR/MUC1NCT04695847Phase 1M1231
EpCAM/CD3NCT04501744Phase 1M701
FRα/TRPV6NCT04740398Phase 1CBP-1008
GPC3/CD3NCT02748837Phase 1ERY974
HER2NCT03842085Phase 1MBS301
HER2NCT05320874Phase 1KM257
HER2NCT04040699Phase 1KN026 and KN046
HER2NCT03821233Phase 1ZW49
HER2NCT02892123Phase 1Zanidatamab
HER2NCT05380882Phase 1TQB2930
HER2 + PD-1/CTLA-4NCT02760199Phase 189Zr-AMG211
HER2/4-1BBNCT03330561Phase 1PRS-343
HER2/4-1BBNCT03650348Phase 1PRS-343
HER2/HER3NCT00911898Phase 1MM-111
HER2/HER3NCT01304784Phase 1MM-111
HER2/SIRPαNCT05076591Phase 1IMM2902
HLA-A*02NCT05359445Phase 1IMA401
HLA-G/CD3NCT04991740Phase 1JNJ-78306358
Mesothelin/CD47NCT05403554Phase 1NI-1801
OX-40/4-1BBNCT04648202Phase 1FS120
PD-1NCT05263180Phase 1EMB-09
PD-1NCT05089266Phase 1CAR T cells
PD-1NCT05373147Phase 1PD1-MSLN-CAR T cells
PD-1NCT04503980Phase 1PD1-MSLN-CAR T cells
PD-1NCT04489862Phase 1PD1-MSLN-CAR T cells
PD-1/CTLA-4NCT04606472Phase 1SI-B003
PD-1/CTLA-4NCT04572152Phase 1AK104
PD-1/CTLA-4NCT05293496Phase 1Lorigerlimab
PD-1/CTLA-4NCT03530397Phase 1MEDI5752
PD-1/CTLA-4NCT03761017Phase 1Lorigerlimab
PD-1/CTLA-4NCT03517488Phase 1XmAb20717
PD-1/HER2NCT04162327Phase 1IBI315
PD-1/ICOSNCT03752398Phase 1XmAb23104
PD-1/LAG-3NCT04140500Phase 1RO7247669
PD-1/LAG-3NCT03219268Phase 1Tebotelimab
PD-1/LAG-3NCT05645276Phase 1AK129
PD-1/LAG-3NCT05577182Phase 1INCA32459-101
PD-1/PD-L1NCT03936959Phase 1LY3434172
PD-1/PD-L1NCT04672928Phase 1IBI318
PD-1/PD-L1NCT04777084Phase 1IBI318
PD-1/TGF-βNCT05028556Phase 1Y101D
PD-1/TIM-3NCT03708328Phase 1RO7121661
PD-1/TIM-3NCT05357651Phase 1LB1410
PD-1/VEGFNCT04047290Phase 1AK112
PD-1/VEGFNCT05116007Phase 1AK112
PD-L1/4-1BBNCT04009460Phase 1ES101
PD-L1/4-1BBNCT04762641Phase 1ABL503
PD-L1/4-1BBNCT03809624Phase 1INBRX-105
PD-L1/4-1BBNCT04740424Phase 1FS222
PD-L1/4-1BBNCT03922204Phase 1MCLA-145
PD-L1/CD27NCT04440943Phase 1CDX-527
PD-L1/CD37NCT04881045Phase 1PF-07257876
PD-L1/CD47NCT04912466Phase 1IBI322
PD-L1/CD47NCT04328831Phase 1IBI322
PD-L1/CD47NCT05200013Phase 1BAT7104
PD-L1/LAG3NCT05101109Phase 1BL501
PD-L1/OX-40NCT05638334Phase 1S09501
PD-L1/TGF-βNCT04958434Phase 1TST005
PD-L1/TGF-βNCT05537051Phase 1PM8001
PD-L1/TGF-βNCT04954456Phase 1QLS31901
PD-L1/TIM-3NCT03752177Phase 1LY3415244
PD-L1/VEGFNCT05650385Phase 1B1962
PSMANCT03927573Phase 1GEM3PSCA
SSTR2/CD3NCT03411915Phase 1XmAb18087
TIGIT/PVRIGNCT05607563Phase 1PM1009
Tregs antigensNCT04156100Phase 1AGEN1223
CD3/5T4NCT04424641Phase 1/2GEN1044
CD3/5T4NCT05180474Phase 1/2GEN1047
CD3/GD2NCT04750239Phase 1/2Nivatrotamab
CEA/HSGNCT01221675Phase 1/2TF2
DLL4/VEGFNCT04492033Phase 1/2CTX-009 (ABL001)
EGFR/CD16ANCT05099549Phase 1/2AFM24
EGFR/CD16ANCT04259450Phase 1/2AFM24
EGFR/CD28NCT04626635Phase 1/2REGN7075
EGFR/CD3NCT04844073Phase 1/2MVC-101 (TAK-186)
EGFR/cMetNCT04868877Phase 1/2MCLA-129
EGFR/cMetNCT04930432Phase 1/2MCLA-129
EGFR/cMETNCT05498389Phase 1/2EMB-01
EGFR/cMETNCT04590781Phase 1/2XmAb18087
EGFR/CmetNCT03797391Phase 1/2EMB-01
EpCAM/CD3NCT05543330Phase 1/2M701
GD2/CD3NCT03860207Phase 1/23F8
GD2/CD56NCT05437328Phase 1/2bi-4SCAR GD2/CD56 T cells
GD2/CD70NCT05438368Phase 1/2bi-4SCAR GD2/CD70 T cells
GD2/PSMANCT05437315Phase 1/2bi-4SCAR GD2/PSMA T cells
HER2/4-1BBNCT05523947Phase 1/2YH32367
NY-ESO-1/LAGE-1ANCT03515551Phase 1/2IMCnyeso
PD-1/CTLA-4NCT04172454Phase 1/2AK104
PD-1/CTLA-4NCT03852251Phase 1/2AK104
PD-1/CTLA-4NCT05559541Phase 1/2AK104
PD-1/CTLA-4NCT05235542Phase 1/2AK104
PD-1/CTLA-4NCT05505825Phase 1/2AK104
PD-1/LAG-3NCT04618393Phase 1/2EMB-02
PD-1/TIGITNCT04995523Phase 1/2AZD2936
PD-1/TIM-3NCT04931654Phase 1/2AZD7789
PD-1/VEGFNCT04597541Phase 1/2Ivonescimab
PD-1/VEGFNCT05689853Phase 1/2Ivonescimab
PD-1/VEGFNCT05229497Phase 1/2Ivonescimab
PD-1/VEGFNCT05214482Phase 1/2Ivonescimab
PD-1/VEGFNCT04900363Phase 1/2Ivonescimab
PD-L1/4-1BBNCT05159388Phase 1/2PRS-344/S095012
PD-L1/4-1BBNCT04841538Phase 1/2ES101
PD-L1/CTLA-4NCT05425602Phase 1/2MAX-40279-01
PD-L1/LAG-3NCT03440437Phase 1/2FS118
PRAME/CD3NCT04262466Phase 1/2IMC-F106C
PSMA/CD3NCT04496674Phase 1/2CC-1
PSMA/CD70NCT05437341Phase 1/2bi-4SCAR PSMA/CD70
TIGIT/PD-L1NCT05102214Phase 1/2HLX301
TIGIT/PD-L1NCT05390528Phase 1/2HLX301
CD3/MUC1NCT03501056Phase 2CD3-MUC1 Bispecific Antibody
EGFR/CmetNCT05299125Phase 2Amivantamab
HER2/HER3NCT02912949Phase 2Zenocutuzumab
HER2/HER3NCT05588609Phase 2Zenocutuzumab
Her-2Neu/EpCAM NCT00149019Phase 2Cell therapy
PD-1/CTLA-4NCT04547101Phase 2AK104
PD-1/CTLA-4NCT05377658Phase 2AK104
PD-1/CTLA-4NCT05420220Phase 2KN046
PD-1/CTLA-4NCT05215067Phase 2AK104
PD-1/VEGFNCT04736823Phase 2AK112
PD-1/VEGFNCT05247684Phase 2AK112
PD-L1/4-1BBNCT05117242Phase 2GEN1046
EpCAM/CD3NCT00836654Phase 2/3Catumaxomab
EGFR/CMETNCT05388669Phase 3Amivantamab
CLDN18.2NCT05436093Not applicable18F-FDG
HER2/HER3NCT04100694Not applicableMCLA-128
PD-L1NCT05156515Not applicable68Ga-THP-APN09
TAA/CD3 or CD28NCT05119257Not applicable
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Arasanz, H.; Chocarro, L.; Fernández-Rubio, L.; Blanco, E.; Bocanegra, A.; Echaide, M.; Labiano, I.; Huerta, A.E.; Alsina, M.; Vera, R.; et al. Current Indications and Future Landscape of Bispecific Antibodies for the Treatment of Lung Cancer. Int. J. Mol. Sci. 2023, 24, 9855. https://doi.org/10.3390/ijms24129855

AMA Style

Arasanz H, Chocarro L, Fernández-Rubio L, Blanco E, Bocanegra A, Echaide M, Labiano I, Huerta AE, Alsina M, Vera R, et al. Current Indications and Future Landscape of Bispecific Antibodies for the Treatment of Lung Cancer. International Journal of Molecular Sciences. 2023; 24(12):9855. https://doi.org/10.3390/ijms24129855

Chicago/Turabian Style

Arasanz, Hugo, Luisa Chocarro, Leticia Fernández-Rubio, Ester Blanco, Ana Bocanegra, Miriam Echaide, Ibone Labiano, Ana Elsa Huerta, Maria Alsina, Ruth Vera, and et al. 2023. "Current Indications and Future Landscape of Bispecific Antibodies for the Treatment of Lung Cancer" International Journal of Molecular Sciences 24, no. 12: 9855. https://doi.org/10.3390/ijms24129855

APA Style

Arasanz, H., Chocarro, L., Fernández-Rubio, L., Blanco, E., Bocanegra, A., Echaide, M., Labiano, I., Huerta, A. E., Alsina, M., Vera, R., Escors, D., & Kochan, G. (2023). Current Indications and Future Landscape of Bispecific Antibodies for the Treatment of Lung Cancer. International Journal of Molecular Sciences, 24(12), 9855. https://doi.org/10.3390/ijms24129855

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