Bispecific antibodies (bsAbs) directed against PD-1/PD-L1 and CTLA-4;a mini review

Abstract

Novel approaches to tumor immunotherapy include adoptive cell immunotherapy, immune checkpoint inhibitors (ICIs), and bispecific antibodies (bsABs). bsABs are members of the antibody family that have the ability to distinguish between two distinct antigens or epitopes on a single antigen. These antibodies show better clinical results than monoclonal antibodies, suggesting that they might be a useful choice for tumor immunotherapy. Additionally, dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 functions at various phases of T cell activation with synergistically increasing immune responses against cancer cells, in contrast to ICI monotherapy, which sometimes displays treatment resistance and limited effectiveness. It has been shown that immune response rates and anti-tumor effects may be increased in a synergistic manner by ICI-based combination therapy. We explore the safety and effectiveness of bsABs and ICIs (especially PD1/PDL1 and CTLA-4) combination treatments in tumor immunotherapy in this study with the goal of offering evidence-based methods for clinical research and tailored tumor identification and management.

Keywords

Bispecific antibodies (bsABs)PD1/PDL1 CTLA-4 combination therapy

Introduction

Bispecific antibodies (bsABs) have been a unique approach to tumor immunotherapy in recent years. In contrast to naturally occurring antibodies, many bsAbs are manufactured using biochemical or genetic engineering techniques,¹ while some, like Catumaxomab, the first bsAb to get clinical approval, are made utilizing hybrid-hybridoma technology.² Combining two different antigen targets into one antibody molecule has the potential to improve clinical effectiveness and safety of bsABs. They come in a variety of forms and may be classified into IgG-like and non-IgG-like antibodies based on the presence or lack of the Fc region. While some bsAbs use scFvs for antigen binding, others use Fab fragments, single-domain antibodies (sdAbs) such as VHH domains (nanobodies), or other antibody fragments that lack the Fc region, allowing for smaller, more focused bsAbs without the entire IgG structure.^3,4 The development and broad use of bsABs have been expedited by this dual targeting strategy.⁵ The term “dual targeting” describes how bsAbs may bind two distinct antigens or epitopes at the same time, boosting immune responses by increasing tumor specificity, decreasing immune escape, and modifying important signaling pathways. When bsABs were first used for hematologic malignancies, they demonstrated notable clinical effectiveness and helped the majority of patients achieve complete remission (CR). The therapeutic effectiveness of CD19/CD3 and CD20/CD30 bsABs in non-hodgkin's lymphoma patients was shown to be higher for indolent follicular lymphoma than for diffuse large B-cell lymphoma (DLBCL).^6–12 Even while bsABs had a somewhat lower CR (9%) than PD-1/LAG-3, the early clinical trial findings provide novel treatment opportunities for the management of DLBCL patients.¹³ When treating patients with Hodgkin's lymphoma (HL), better response rates were linked to the use of CD30/CD16A bsABs in conjunction with pembrolizumab (ORR, 83%) and ICI combination treatments (ORR, 74%).^14–17

As shown by earlier research, ICI monotherapy has a limited degree of therapeutic effectiveness.^18,19 On the other hand, whereas dual ICI combination therapy improves survival advantages, it also comes with a higher risk of treatment-related adverse events (TRAEs) and other limitations.²⁰ With the development of bsAbs, there is now a new alternative for cancer therapy that may both lessen treatment-related toxicity and improve immunotherapy's effectiveness. There are now many different bsAbs used in cancer immunotherapy, such as Belantamab mafodotin (Blenrep),²¹ blinatumomab (Blincyto),²² and mosunetuzumab (Lunsumio).⁹ Among the most developed targets within ICIs, PD-1/PD-L1 and CTLA-4 are the subject of much investigation due to their potential use in cancer immunotherapy using bsAbs that target these checkpoints. A multitude of research facilities throughout the globe have conducted comprehensive investigations into the synergistic use of ICI treatments and bsABs in the treatment of solid tumors and hematological malignancies. Our goal in writing this study is to provide an overview of these immunotherapies’ side effects and effectiveness.

Bsabs directed against CTLA-4 and Pd-L1

KN046 is a novel bsAb targeting PD-L1 and CTLA-4, capable of inhibiting the interactions between PD-L1 and PD-1, as well as between CTLA-4 and CD80/CD86.²³ Yuxiang Ma et al.²⁴ conducted the first large phase I study of KN046, a bispecific antibody, with dual inhibition of PD-L1 and CTLA-4 in advanced solid tumors. According to their findings, KN046 monotherapy exhibited a low incidence of grade 3 TRAEs, a good safety profile, and was well tolerated. Furthermore, KN046 demonstrated possible survival advantages in several tumor types (longer OS and a median DOR of 16.6 months). Using a thorough approach based on the pharmacokinetic–pharmacodynamic model, preliminary exposure–response analysis, and overall safety profile, the RP2D of KN046 monotherapy was established as 5 mg/kg Q2 W.²⁴ Moreover, phase II trial (NCT03872791) conducted by Qiao Li et al.²⁵ attempts to assess the safety and effectiveness of nab-paclitaxel with anti-PD-L1/CTLA-4 bispecific antibody KN046 as a first-line therapy for patients with metastatic triple-negative breast cancer (TNBC). Regardless of PD-L1 expression status, the good response was sustained among the response-evaluable patients, and the clinical effectiveness reported was favorable with an ORR of 44.0%. The first-line therapy of KN046 + nab-paclitaxel is beneficial for unselected advanced TNBC patients. Among the intention-to-treat (ITT) group, this treatment had a median PFS of 7.33 months and a median OS of 30.92 months.²⁵ In a phase 2 study, patients with squamous non-small cell lung cancer (NSCLC) get paclitaxel in addition to KN046 and carboplatin, whereas those with non-squamous NSCLC receive pemetrexed. The median response time is 8.1 months, and the objective response rate is 46.0%. These results suggest that KN046 and chemotherapy as first-line treatments are safe and effective for patients with metastatic NSCLC.²⁶ The Phase II research also evaluated KN046's safety and effectiveness in treating advanced NSCLC patients who had not responded to platinum-based chemotherapy or were resistant to it. The ORRs for the 3 mg/kg and 5 mg/kg groups, according to the data acquired, were 13.3% and 14.7%, respectively. The overall survival rate was 13.04 months and the median progression-free survival was 3.68 months.²⁷ In patients with advanced NSCLC who had either not responded to platinum-based chemotherapy or had developed resistance to it, this research verified that both KN046 dosage regimens demonstrated encouraging safety and effectiveness.

Bsabs directed against Pd-1 and CTLA-4

QL1706

QL1706 (PSB205) is a bispecific antibody with two functions: it is an engineered monoclonal antibody against CTLA-4 IgG1 and an anti-PD-1 IgG4 antibody.²⁸ Additionally, the use of a revolutionary MabPair technology platform makes it possible to produce two antibodies that are made as a single product and closely resemble their natural forms from a single host cell.²⁹

QL1706 was tested for safety and effectiveness in patients with advanced solid tumors who had not responded to conventional treatment in the first Phase I/Ib clinical study.²⁹ It was shown that QL1706 was well tolerated, as only 83 subjects (16%) had TRAEs of grade ≥3. Furthermore, it demonstrated strong anticancer effect against many cancer types, particularly in individuals with cervical and NPC who had not had any prior immunotherapy.²⁹ This clinical study demonstrated acceptable tolerability while confirming the anti-tumor effectiveness of QL1706 in solid tumors, especially in patients with nasopharyngeal carcinoma, cervical cancer, and non-small cell lung cancer. For advanced NSCLC, a phase II trial showed promising results with first-line QL1706 with chemotherapy, either with or without bevacizumab. With a median duration of response (mDOR) of not reached (NR) and an ORR of 45%, this regimen demonstrated a promising and sustained response. Furthermore, mPFS marginally preferred the 4-cycle QL1706 plus chemotherapy with bevacizumab regimen in the group with non-squamous NSCLC, hence endorsing its future exploration in phase III trials.³⁰ Further findings are eagerly awaited from ongoing randomized Phase II and III (NCT05179317, NCT05576272, NCT05487391, and NCT05446883) studies.

Cadonilimab (AK104)

AK104, also known as codonilimab, is a humanized bsAb that targets CTLA-4 and PD-1. PD-1 and CTLA-4 expressed on tumor-infiltrating lymphocytes (TILs) are concurrently bound by this symmetric tetravalent bifunctional antibody with high affinity, resulting in a co-targeting effect that improves anti-tumor activity while increasing safety.^31,32 In advanced NSCLC patients who had previously had platinum-based doublet chemotherapy with or without immunotherapy, Zhao et al.³³ conducted a thorough assessment of the safety and effectiveness of cadonilimab for the first time. The study's main goal was not achieved: cadonilimab monotherapy again showed little benefit, particularly in terms of response rate, for patients who had developed both primary and acquired resistance to prior immunotherapy. Nonetheless, after the failure of platinum-based doublet chemotherapy, it could play a part as a second-line immunotherapy monotherapy.³³ In another study, there were no dose-limiting effects during dosage escalation. The objective response rate in phase 2 of the cervical cancer cohort was 32·3%, with a median follow-up of 14·6 months. Also, in the group of patients with hepatocellular carcinoma, the objective response rate was 16·7% after a median follow-up of 19·6 months. The objective response rate in the cohort of patients with oesophageal squamous cell carcinoma was 18·2%, with a median follow-up of 17·9 months. In light of this, it may be concluded that cadonilimab has the potential to treat advanced solid tumors due to its positive tumor response rate and manageable toxicity profile.³⁴

Numerous clinical studies are now in progress, including AK104-208 (NCT04646330) and AK104-207 (NCT04647344). It is expected that the results of these studies will clarify the function of cadonilimab in the treatment of lung cancer and maybe provide new guidelines for treatment protocols.

Volrustomig (MEDI5752)

Volrustomig (MEDI5752) is intended to totally block PD-1 while selectively inhibiting CTLA-4 on activated PD-1⁺ T cells.³⁵ Volrustomig showed significant clinical activity in patients with solid tumors, a satisfactory safety profile, long-term PD-1 receptor occupancy, and T cell proliferation at levels higher than those observed with clinically acceptable doses of CTLA-4 inhibitors and anti-PD(L)-1 co-administration in an FTiH trial.³⁶ MEDI5752 monotherapy 2.25–2500 mg intravenously every 3 weeks demonstrated encouraging antitumor activity in advanced solid tumors in a phase I, open-label study (MedImmune LLC, NCT03530397).³⁷ It was reported that at doses greater than 225 mg, Volrustomig produced dose-dependent peripheral pharmacodynamic alterations of biomarkers unique to CTLA-4 inhibition. Increases in CD4 T cell proliferation, activation, and memory T cells were reported at C1D8 with dosages ≥ 500 mg; these increases were all larger than those observed in historical controls of patients treated with durvalumab and tremelimumab 3 mg/kg. Furthermore, compared to durvalumab alone, the historical control, volrustomig enhanced CD8 proliferation in the tumor.³⁶ Also, in an early phase research, the bispecific antibody Volrustomig (MEDID5752), which targets CTLA-4 and PD-1, was assessed for advanced ccRCC that had not been treated. Patients in the expansion phase were randomized to either 500 mg of volrustomig or 750 mg of the drug. The greater dosage of volrustomig was linked to a higher frequency of grade 3 or 4 treatment-related toxicities (63% vs. 42%), even though it produced a higher DCR than the lower dose (90% vs. 70%).³⁸ Moreover, a phase 1/2 trial indicated clinical effectiveness and overall tolerability in the treatment of renal cell carcinoma (RCC) and NSCLC (NCT03530397), and a follow-up phase III research, eVOLVE-HNSCC, is currently enrolling to evaluate volrustomig as an adjuvant therapy following chemoradiation for locoregional illness.³⁹

Rilvegostomig (AZD2936)

AZD2936 is a humanized, bispecific IgG1 that targets TIGIT and PD-1. ARTEMIDE-01 (NCT04995523), the first human trial, assessed the medication in an open-label multicenter study that included patients with advanced NSCLC whose PD-L1 TPS was > 1%. Dosage escalation, tolerance, expansion safety, dose-limiting toxicities, and initial efficacy were all investigated.^40,41 Adenocarcinoma affected 72.5% of the 80 patients who were recruited, metastases affected 96.3%, and brain metastases affected 22.5%. The median length of treatment was eleven weeks. The most common TRAEs were lipase increase, rash, and pruritus (6.3% each). Three patients (3.8%) had severe TRAEs, including tiredness, acute hepatitis, and immune system issues. In 76 evaluable patients, 30 stable illnesses and 3 partial responses were observed.⁴⁰ The current clinical development of AZD2936 in cancer patients is supported by preclinical outcomes. AzD2936 was shown to bind TIGIT and PD-1 with high affinity both separately and simultaneously, blocking interaction with their respective main ligands, CD155 and PD-L1.⁴² Compared to anti-PD-1 therapy, the bispecific antibody increased IFN-γ release and induced antigen-specific T cell-mediated lysis of tumor cell lines. AZD2936 increased tumor cell death when antigen-specific T lymphocytes were co-cultured in a tumor spheroid model. Additionally, AZD2936's efficacy was examined in two human cancer xenograft mice models. When AZD2936 was administered to mice in these models, tumor development was considerably reduced in comparison to controls and a combination of parental antibodies.⁴² As a result, AZD2936 is a new immunotherapy that targets TIGIT and PD-1 and may improve anti-tumor immunity.

Combination of BsAbs/ICIs with targeted therapy

Through interference with certain molecular targets, targeted cancer treatment aims to reduce the development, progression, and metastasis of cancer.⁴³ This therapy method is revolutionary since it involves decreasing metastasis, inducing apoptosis, preventing tumor angiogenesis, encouraging tumor cell differentiation, preventing tumor cell proliferation, and interfering with the cell cycle.⁴⁴ But a major obstacle that targeted therapy now confronts is that a sizable portion of patients become resistant to the medication. According to recent research, targeted cancer treatment may cause tumor cells to undergo immunogenic cell death (ICD), which increases the effectiveness of ICIs.^44,45 ICD is a kind of controlled cell death that initiates an anti-tumor immune response by producing damage-associated molecular patterns (DAMPs), which excite dendritic cells and activate T cells.⁴⁵ bsAbs can trigger ICD by stimulating lysis of tumor cell and enhancing antigen presentation to activate an anti-tumor immune response. This finding has made it possible to combine immunotherapy with targeted cancer treatment, providing a novel strategy to improve clinical effectiveness and overcome drug resistance. The therapeutic effectiveness of vemurafenib and cobimetinib in combination with atezolizumab, an anti-PD-L1 monoclonal antibody, was evaluated in patients with advanced or metastatic melanoma containing BRAF V600 mutations via the Phase III clinical trial (NCT02908672).⁴⁶ The results of the trial showed that atezolizumab was a safe and tolerated addition to targeted treatment with vemurafenib and cobimetinib, which substantially enhanced progression-free survival in patients with advanced melanoma that was positive for the BRAFV600 mutant.⁴⁶ Moreover, combination of olaparib and durvalumab treatment was evaluated for its effectiveness in treating patients with metastatic breast cancer who had germline BRCA1 or BRCA2 mutations in the Phase I/II MEDIOLA research. The most frequent adverse events that occurred in 11 (32%) individuals were anemia, neutropenia, and pancreatitis. At 12 weeks, 24 (80%) of the 30 patients eligible for activity analysis achieved disease control; there were no treatment-related fatalities. In line with earlier findings from olaparib and durvalumab monotherapy trials, the combination of olaparib with durvalumab demonstrated encouraging antitumor efficacy and safety. To find out what factors predict therapeutic benefit and if adding durvalumab to olaparib monotherapy improves long-term clinical outcomes, further study in a randomized context is required.⁴⁷

Many clinical studies investigating the use of bsAbs in conjunction with targeted medicines are now underway (NCT04777084, NCT04646330, NCT05816499, and NCT05420220).

Future perspective and conclusion

By avoiding the TME's immunological tolerance and specifically targeting certain immune inhibitory checkpoints, BsAbs may reduce the immunosuppressive phenotype.^48,49 Moreover, bsAbs that target co-stimulatory molecules have the ability to enhance immunological responses mediated by T cells.^50,51 The ability to cross-link two different kinds of cells or bind two molecules in cis on the cell membrane is a special benefit provided by bsAbs. bsAbs may lessen TRAEs and eliminate off-target effects in normal tissues by altering the affinity of the two binding sites.^52,53 Their capacity for dual targeting not only increases their therapeutic potential but also provides a more focused strategy that lowers collateral harm and raises the specificity of cancer therapies. By lowering toxicity and the frequency of TRAEs, the creation of bsAbs seeks to improve therapeutic effectiveness via developments in antibody engineering technology.^54,55 Similar to dual blockade immunotherapy, both bsAbs and dual ICI combination treatment target two targets at once, boosting the tumor immune response and producing a more profound impact than just additive one. The combined treatment is far more effective than monotherapy. On the other hand, although response rates are increased, the dual ICI combination treatment may raise the chance of TRAEs.

There are many limitations on the dosage, effectiveness, and indications of both fixed antibody valency in bsAbs and fixed drug pairing in dual ICI combination treatment. Predictive biomarkers including PD-L1 expression and tumor mutational load can guide treatment choices, making patient selection for bsAb therapy essential. To balance toxicity and effectiveness, dosage techniques must be optimized, which often calls for step-up dose regimens. Clinical results may also be improved by sequencing bsAb treatment with checkpoint inhibitors or other immunotherapies. Furthermore, these restrictions impede the creation of novel therapeutic approaches, such chemotherapy and radiation combination treatments. Choosing the best treatment plans is crucial as the number of targeted medications and drug combinations increases. Predictive biomarker investigation is desperately needed in order to target certain immunological traits. In summary, although the successful implementation of immunotherapy presents a substantial obstacle, we remain optimistic and believe that the ongoing research on bsABs will further our comprehension of ICI combination therapies in the context of tumor immunotherapy. Advances in understanding will ultimately assist a larger range of cancer patients by improving the clinical effectiveness and safety of various therapeutic options.

Footnotes

Acknowledgments

This study was supported by the Vice Chancellor for Research and Technology of Tabriz University of Medical Sciences, Tabriz, Iran

ORCID iDs

Amirhossein Mardi

Leili Aghebati-Maleki

Ethics approval and consent to participate

Not applicable.

Authors’ contributions

Amirhossein Mardi drafted the main text. Leili Aghebati-Maleki supervised the work and provided the comments and additional scientific information. All authors read and approved the final version of the work to be published.

Consent for publication

Not applicable.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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