B7 Homolog 4 (B7-H4)-Directed Agents in Oncology Clinical Trials: A Review

Abstract

B7 homolog 4 (B7-H4) is a transmembrane protein found on immune cells and is frequently overexpressed in various solid tumors, making it a promising target for cancer therapy. B7-H4–directed agents, particularly antibody-drug conjugates (ADCs) like puxitatug samrotecan (AZD8205), felmetatug vedotin (SGN-B7H4V), and GSK5733584, have demonstrated early clinical activity with promising response rates in triple-negative breast cancer (TNBC). Combination strategies, such as ADCs with anti–PD-1 or PARP inhibitor therapies, have also shown enhanced tumor regression in preclinical models and are the subject of several ongoing clinical trials. This review highlights the current landscape of B7-H4–targeted agents, their progress in clinical trials, and the potential for combination approaches to improve outcomes in B7-H4–expressing cancers.

INTRODUCTION

B7 homolog 4 (B7-H4), also known as DD-O110, B7x, B7S1 (B7 superfamily member 1), and VTCN1 (V-set domain containing T-cell activation inhibitor 1), is a type I transmembrane glycoprotein within the B7 family of immune checkpoint proteins. Under normal physiological conditions, B7-H4 is primarily expressed in antigen-presenting cells (APCs), where it functions as a negative regulator of T-cell immunity.[1] B7-H4 fine-tunes the immune response and functions as part of a broader network of inhibitory molecules that work collectively to regulate T-cell response.[2] By binding to a yet-unidentified receptor on activated T cells, B7-H4 inhibits phosphorylation of mitogen-activated protein (MAP) kinases, including ERK, p38, JNK, and AKT.[3] Suppression of associated pathways ultimately leads to reduced T-cell proliferation and interleukin (IL)-2 production (Fig. 1).[3 ,4]

Figure 1.

T-cell interaction with antigen-presenting cells (APC) and tumor cells. (A) Normal physiologic response to the interaction of B7-H4 on APC with T cells.

1: B7-H4 promotes regulatory T cells, which then reduce effector T-cell cytotoxicity and increase T-cell apoptosis via suppression of ERK-, p38-, JNK-, and AKT-associated pathways.[3]

2: B7-H4 inhibits T-cell proliferation via the above pathways due to decreased IL-2 production.[3 ,4] (B) Pathologic response of the interaction between B7-H4 on tumor cells with T cells.

3: B7-H4 promotes TAM populations with IL-6 and IL-10, resulting in increased tumor growth and immune evasion.[4 ,32]

APC: antigen presenting cell; IL: interleukin; TAM: tumor-associated macrophage; TGF: tumor growth factor; VEGF: vascular endothelial growth factor. Adapted from Dawidowicz et al.[4]

B7-H4 overexpression promotes immune suppression by driving T-cell exhaustion, increasing regulatory T cells, and recruiting tumor-associated macrophages (TAMs), which collectively facilitate tumor progression and immune evasion.[5-8]. Although B7-H4 overexpression is observed across many tumor types, its reported prevalence in tumor cells varies widely, ranging from 2% in small-cell lung cancers to 94% in ovarian serous carcinomas.[4] B7-H4 overexpression in ovarian, triple-negative breast cancer (TNBC), gastric, and pancreatic cancers has been associated with tumor progression, drug resistance, and unfavorable prognosis.[4 ,5,9] A comprehensive overview of B7-H4 expression across various malignancies is provided in Table 1.

Table 1.

B7-H4 expression rate in solid tumors

Tumor Type	Expression (%)
Ovarian	94.5
Adenoid cystic carcinoma	94
Breast (TNBC)	90
Endometrial	71.5
Breast (HR−/HER2+)	60
Renal cell carcinoma	60
Glioma	54.1
Salivary gland carcinoma	50
Cholangiocarcinoma	49.1
Bladder	49
Lung adenocarcinoma	44.9
Breast (HR+/HER2+)	25
Small cell lung cancer	2.6–6.8
Gallbladder	57–69
Gastric	44.9–80
Cervical	44.8–80.56
Esophageal	53.8–95.5
Colorectal	29.1–80
Pancreatic	22.1–76
Hepatocellular carcinoma	1–73

Based on information from Dawidowicz et al.[4]

HR: hormone receptor; TNBC: triple-negative breast cancer.

Given its apparent role in promoting tumor immune evasion, B7-H4 has emerged as a promising therapeutic target. Antibody-drug conjugates (ADCs) with B7-H4–targeted payloads have shown potent in vitro cytotoxicity, including cell cycle arrest, DNA damage, and significant tumor regression.[10 ,11] In vivo, the ADC emiltatug ledadotin (XMT-1660) exhibited dose-dependent antitumor activity, with complete tumor regression observed in breast and ovarian cancer xenograft models.[10] Another ADC, felmetatug vedotin (SGN-B7H4V), exhibited enhanced efficacy when combined with PD-1 inhibitors, suggesting a synergistic potential in combination therapies.[12] Additionally, a B7-H4/CD3 bispecific antibody demonstrated strong CD8+ T-cell–mediated tumor reduction with a favorable safety profile.[13] These findings underscore the promising role of B7-H4–targeted therapies in cancer treatment, both as monotherapies and in combination with immune checkpoint inhibitors.

The promising outcomes from preclinical studies have led to the initiation of clinical trials aimed at evaluating the safety and efficacy of B7-H4–targeted therapies across various cancers. This clinical review aims to compile and summarize the current findings from publicly available conference abstracts, published studies, and clinical trial databases to provide an overview of ongoing efforts in B7-H4–targeted therapy development (Table 2).

Table 2.

B7-H4-targeted agent clinical trials with published data.

Treatment Type	Drug Name and Trial No.	Trial Phase	Tumor Type	Mechanism	MTD/RP2D	DLTs	Most Common Toxicities	N	Biomarker Examined
Antibody Drug Conjugate (ADC)	Felmetatug vedotin (SGN-B7H4V)[14,15] NCT05194072	I – dose escalation	Advanced solid tumors	MMAE payload, DAR 4	NA	1.25 mg/kg: hyperglycemia 1.5 mg/kg: arterial embolism, neutropenia, peripheral sensory neuropathy 2.0 mg/kg: transaminitis	Fatigue (20.0%), peripheral sensory neuropathy (20%), neutropenia (14.3%)	75	ADAs
	GSK-5733584 (HS-20089)[16,38] NCT05263479	I – dose escalation	Advanced solid tumors	Top1i payload, DAR 6	4.8–5.8 mg/kg potential therapeutic target dose	7.2 mg/kga	Leukopenia, neutropenia, nausea, anemia, thrombocytopenia, vomiting, fatigue, transaminitis, hyponatremiab	44	ADAs
	Puxitatug samrotecan (AZD-8205)[17,18] NCT05123482 (BLUESTAR)	I – dose escalation	Advanced solid tumors	Top1i payload, DAR 8	NA	3.2 mg/kg: neutropenia, thrombocytopenia	Nausea (58.7%), neutropenia (56.5%), anemia (50.0%)	46	ADAs
Monoclonal Antibody (mAb)	Alsevalimab (FPA-150)[22,23] NCT03514121 Terminated	Ia	Dose escalation: Advanced solid tumors Dose exploration: B7-H4+ solid tumors	Humanized, afucosylated IgG1 mAb	20 mg/kg (RP2D)	None	Diarrhea (16.7%), fatigue (13.8%)	21 8	ADAs
	NC-762[24,25] NCT04875806 Terminated	I/II	Advanced solid tumors	Humanized IgG1κ mAb	NA	None	None	14	NA

^aFurther data not reported.

^bPercentages not reported.

ADAs: anti-drug antibodies; AF-HPA: auristatin F-hydroxypropylamide; DLTs: dose-limiting toxicities, DAR: drug antibody ratio; mAb: monoclonal antibody; MMAE: monomethyl auristatin E; MTD: maximum-tolerated dose; RP2D: recommended Phase II dose; Top1i: topoisomerase I inhibitor.

METHODS

A literature search was completed on November 19, 2024, focusing on the role of B7-H4 in oncology and the development of B7-H4–targeted therapies. Search terms on PubMed and ClinicalTrials.gov included “B7 homolog 4,” “B7-H4,” “B7H4,” “B7S1,” “B7-S1,” “B7x,” “VTCN1,” and “DD-O110.” Articles were screened for relevance based on their titles and abstracts. Articles addressing B7-H4 expression on solid tumors, its role in cancer, or relevant therapeutic advances were included. Additionally, a Google search was conducted to identify presentations and posters from conferences, including the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Society for Immunotherapy of Cancer (SITC). Searches were filtered to include conference materials focused on preclinical studies, clinical trial updates, or mechanisms of action involving B7-H4–targeted agents. The final literature selection consisted of peer-reviewed articles and conference abstracts directly related to the therapeutic potential of B7-H4–directed therapies.

Antibody-Drug Conjugates (ADCs)

Felmetatug vedotin

Felmetatug vedotin (previously SGN-B7H4V, PF-08046048; Pfizer, USA; previously Seagen, USA) is an investigational ADC using a monomethyl auristatin E (MMAE) payload. This ADC is currently being evaluated in a phase I dose-escalation clinical trial (NCT05194072) for patients with confirmed locally advanced unresectable or metastatic solid tumor types, including breast, ovarian, endometrial, and biliary tract cancers, irrespective of B7-H4 expression.[14] Part E of the study will separate participants with TNBC into cohorts with a combined positive score (CPS) ≥ 10 or a CPS < 10.[15] This agent was administered on two different schedules as follows: 0.75–1.5 mg/kg every 3 weeks (2Q3W; n = 35) and 0.75–2.0 mg/kg every 4 weeks (2Q4W; n = 40). In the 2Q3W cohort, dose-limiting toxicities (DLTs) were observed in 8.6% (n = 3) and included hyperglycemia at 1.25 mg/kg (n = 1), arterial embolism (n = 1) at 1.5 mg/kg, and neutropenia (n =1) at 1.5 mg/kg. In the 2Q4W cohort, DLTs were reported in 5% (n = 2) and included peripheral sensory neuropathy (n = 1) at 1.5 mg/kg and transaminitis (n = 1) at 2.0 mg/kg. Across both dosing schedules, the most frequent treatment-emergent adverse events (TEAEs) included fatigue (20.0%, n = 15), peripheral sensory neuropathy (20.0%, n = 15), and neutropenia (17.1%, n = 13). The most common TEAE ≥ grade 3 in the 2Q3W cohort was neutropenia (14.3%, n = 5); in the 2Q4W cohort, TEAEs ≥ grade 3 included anemia, dyspnea, hypotension, and pneumonia (5% each, n = 2). Among 65 evaluable patients, partial responses were observed in 28% of breast cancer patients (7/25), 13% of ovarian cancer patients (2/15), 22% of biliary tract cancer patients (2/9), and 6% of endometrial cancer patients (1/16), with a complete response in the endometrial cohort.[14]

GSK5733584

GSK5733584 (alternatively HS-20089; GlaxoSmithKline, UK, in collaboration with Hansoh Pharma, China) is an investigational B7-H4–targeted ADC that employs a topoisomerase inhibitor payload with a drug-antibody ratio (DAR) of 6. GSK5733584 is being evaluated in a first-in-human phase I clinical trial (NCT05263479) in patients with advanced solid tumors.[16] The phase I trial enrolled 44 patients as follows: breast cancer (n = 41), ovarian cancer (n = 2), and endometrial cancer (n = 1). HS-20089 was administered intravenously every 3 weeks (Q3W) at doses ranging from 0.7–7.2 mg/kg. DLTs were observed in two patients at the highest dose level of 7.2 mg/kg, but the abstract did not specify what the DLTs were. The most common TEAEs, observed in ≥ 20% of patients, included leukopenia, neutropenia, nausea, anemia, thrombocytopenia, vomiting, fatigue, elevated alanine aminotransferase, elevated aspartate aminotransferase, anorexia, and hyponatremia. Among the 33 response-evaluable patients, partial response was achieved in 24.2% of patients (n = 8). Among patients with TNBC (n = 16), partial responses were observed in 37.5% (n = 6). Among TNBC patients treated in the potential therapeutic dose range of 4.8–5.8 mg/kg (n = 12), there were partial responses in 41.7% (n = 5).[16]

Puxitatug samrotecan

Puxitatug samrotecan (previously AZD-8205; AstraZeneca, UK) is an investigational B7-H4 ADC using a novel topoisomerase 1 inhibitor (TOP1i) payload with a DAR of 8. This agent is currently in phase I/IIa clinical investigation (NCT05123482; BLUESTAR) for patients with advanced breast, ovarian, endometrial, and biliary tract cancers expressing B7-H4 detected by immunohistochemistry.[17] This clinical trial has two substudies, one evaluating monotherapy and another evaluating a combination with rilvegostomig (previously AZD-2936, a bispecific antibody that inhibits PD-1 and TIGIT).[18] Although results from substudy two have yet to be presented, preliminary results from the phase I dose-escalation portion of substudy one were presented at ESMO 2024. A total of 46 patients received doses ranging from 0.8–3.2 mg/kg, given intravenously Q3W. TEAEs of any grade were observed in 97.8% (n = 45) of patients, including nausea (58.7%, n = 27), neutropenia (56.5%, n = 26), and anemia (50%, n = 23). Grade ≥ 3 TEAEs occurred in 82.6% (n = 38) of patients, with the most common being neutropenia (37%, n = 17) and anemia (30.4%, n = 14). DLTs were reported at the highest dose level of 3.2 mg/kg and included neutropenia (n = 1) and thrombocytopenia (n = 1). Two patients (4.3%) discontinued treatment secondary to TEAEs. Of the patients with ovarian, breast, and endometrial cancer who received doses of ≥ 1.6 mg/kg (n = 43), 20.9% (n = 9) had a partial response.[17]

Early-phase trials without published results

Several ADCs are in early-phase trials and do not yet have data to review (Table 3). These trials are evaluating ADCs for the treatment of advanced solid tumors as either monotherapy or in combination with monoclonal antibodies (mAbs) or bispecific antibodies (bsAbs). BG-C9074, with an undisclosed payload and DAR of 6, is being tested as a monotherapy and in combination with tislelizumab, an anti–PD-1 mAb.[19] Emilatug ledadotin employs an auristatin f-hydroxypropylamide (AF-HPA) payload and is being evaluated as a monotherapy.[20] GSK-5733584, like puxitatug samrotecan, uses a Top1i payload; it is being evaluated as monotherapy and in combination with adebrelimab, an anti–PD-L1 mAb, and bevacizumab, an anti–vascular endothelial growth factor (VEGF) mAb.[21] BLUESTAR is a study evaluating combination therapy with puxitatug samrotecan and relvegostomig, an anti–PD-1/anti-human TIGIT bsAb.[18]

Table 3.

B7-H4–targeted agent clinical trials without published data

Treatment Type	Drug Name	Trial Phase	Tumor Type	Mechanism	Estimated Enrollment (N)	Trial No.
Antibody Drug Conjugate (ADC)	BG-C9074 (DB-1312)[19]	Ia/Ib	Advanced solid tumors	Payload not disclosed, DAR 6	150	NCT06233942
	BG-C9074 (DB-1312)[19] + tislelizumab	Ia	Advanced solid tumors	Payload not disclosed, DAR 6; humanized IgG4 mAb against PD-1	150	NCT06233942
	Emilatug ledadotin[20,39] (XMT-1660)	Ia/Ib	Advanced solid tumors	AF-HPA payload, DAR 6	319	NCT05377996
	GSK-5733584 (HS-20089)[21]	I	Advanced solid tumors	Top1i payload, DAR 6	240	NCT06431594
	GSK-5733584 (HS-20089)[40] + adebrelimab +/− platinuma	I	Advanced solid tumors	Top1i payload, DAR 6; humanized IgG4 mAb against PD-L1	1048	NCT06336707
	GSK-5733584 (HS-20089)[40] + bevacizumab +/− platinuma	I	Advanced solid tumors	Top1i payload, DAR 6; humanized IgG1 mAb against VEGF	1048	NCT06336707
	GSK-5733584 (HS-20089)[41]	II	Advanced ovarian and endometrial cancers	Top1i payload, DAR 6	460	NCT06014190
	Puxitatug samrotecan[18] (AZD-8205)	I/IIa	Advanced solid tumors	Top1i payload, DAR 8	340	NCT05123482 (BLUESTAR)
	Puxitatug samrotecan[18] (AZD-8205) + relvegostomig	I/IIa	Advanced solid tumors	Top1i payload, DAR 8; bsAb against human TIGIT and PD-1	340	NCT05123482 (BLUESTAR)
Monoclonal Antibody (mAb)	Alsevalimab (FPA-150)[22]	Ib	Advanced solid tumors	Humanized, afucosylated IgG1 mAb	95b	NCT03514121 Terminated
	Alsevalimab (FPA-150)[22] + pembrolizumab	Ia	Advanced solid tumors	Humanized, afucosylated IgG1 mAb; humanized IgG4 mAb against PD-1	95b	NCT03514121 Terminated
Bispecific Antibody (bsAb)	ABL-103[28]	I	Advanced solid tumors	bsAb against B7-H4, 4-1BB	96	NCT06126666
	CLN-418[29]	I	Advanced solid tumors	bsAb against B7-H4, 4-1BB	48	NCT05306444
	GEN-1047[27] (DuoBody-CD3-H101GxB7H4)	I/II	Advanced solid tumors	bsAb against B7-H4, CD3	179b	NCT05180474
	PF-07260437[26]	I	Advanced ovarian, endometrial, and B7-H4+ breast cancers	bsAb against B7-H4, CD3	30b	NCT05067972 Terminated

^aCarboplatin or cisplatin.

^bActual enrollment.

AF-HPA: Auristatin F-hydroxypropylamide; bsAb: bispecific antibody; DAR: drug antibody ratio; mAb: monoclonal antibody; PD-1: programmed death 1 receptor; PD-L1: programmed death ligand 1; TIGIT: T-cell immunoreceptor with Ig and ITIM domains; Top1i: topoisomerase I inhibitor; VEGF: vascular endothelial growth factor.

Monoclonal Antibodies (mAbs)

Alsevalimab

Alsevalimab (previously FPA-150; Five Prime Therapeutics, USA) is a humanized, afucosylated IgG1 monoclonal antibody against B7-H4. This agent was studied as monotherapy and in combination with pembrolizumab (an anti–PD-1 agent) in a Phase 1a/1b trial completed in May 2022 (NCT03514121).[22] Final data have not been shared, but a data snapshot presented at ESMO 2019 reported preliminary results. Phase 1a studied dose escalation (n = 21) and dose exploration (n = 8) in patients with gynecological (n = 15), gastrointestinal (n = 7), head/neck (n = 3), genitourinary (n = 2), and other (n = 2) malignancies. As of Mar 15, 2019, no DLTs, treatment-related severe adverse events, or treatment-related adverse events leading to treatment discontinuation were reported. The most common grade 1-2 treatment-related adverse events were diarrhea (16.7%) and fatigue (13.8%). One instance of grade 3 lymphocytopenia was reported at an unspecified dose. Phase 1a successfully resulted in the determination of a 1- to 2-week half-life and a recommended dose of 20 mg/kg for phase 1b monotherapy.[23] The phase 1b portion of the study was terminated in Nov 2024.[22]

NC762

NC762 (NextCure, USA) is a humanized IgG1k monoclonal antibody against B7-H4. As of July 20, 2022, the agent had been studied in a small cohort (n = 14) with five tumor types and a median of six prior therapies. The agent was well tolerated up to 10 mg/kg, and no DLTs, safety concerns, or infusion-related toxicities were observed. Even in the lowest-dose cohorts, a few patients had stable disease beyond 6 months.[24] Ultimately, the study (NCT04875806) was terminated in January 2024 because of limited antitumor activity.[25]

Early-phase trials without published results

Several clinical trials evaluating mAbs and bsAbs have been terminated without data release or are ongoing and have yet to share initial results. A study evaluating alsevalimab monotherapy in combination with pembrolizumab, an anti–PD-1 mAb, was started but terminated in November 2024 without the release of data.[22] Also terminated without data was PF-07260437, a bsAb against B7-H4 and CD3.[26] Other bsAbs undergoing review in clinical trials include ABL-104, CLN-418, and GEN-1047, which target immune checkpoints 4-1BB or CD3.[27–29]

DISCUSSION

To date, 11 different B7-H4–directed agents have entered at least 16 clinical trials for patients with solid tumor cancers. These agents, including ADCs like puxitatug samrotecan, felmetatug vedotin, and GSK-5733584, have shown promising early clinical efficacy across various malignancies, particularly in TNBC, ovarian, endometrial, and gastrointestinal cancers.[14 ,16,17] In the phase 1 trial of puxitatug samrotecan, the observed response rate (ORR) was 20.9% among patients treated within the presumed therapeutic dose range. Among all patients treated on the phase 1 trial of felmetatug vedotin, the ORR was 18.5%, with the highest tumor-specific response rates in breast cancer (ORR = 28%) and biliary tract cancer (ORR = 22%).[14] Despite these encouraging results, responses remain variable, underscoring the need to identify predictive biomarkers and understand mechanisms of resistance.

Trends in safety data reveal that most B7-H4–targeted agents have manageable adverse effects, and, to date, no infusion-related reactions have been reported. Commonly observed toxicities have included fatigue, neutropenia, anemia, neuropathy, and gastrointestinal symptoms (nausea, vomiting, diarrhea). ADC toxicities were consistent with previously documented adverse effects for respective cytotoxic payloads.[11] DLTs for puxitatug samrotecan and GSK-5733584 were primarily hematologic and included neutropenia, thrombocytopenia, leukopenia, and anemia, consistent with previous studies documenting the effects of topoisomerase 1 payloads.[11] The monomethyl auristatin E (MMAE) payload of felmetatug vedotin resulted in peripheral sensory neuropathy and hyperglycemia, consistent with other TEAEs observed in other ADCs containing MMAE.[11]

At this time, all B7-H4–directed agents that have entered clinical trials are administered intravenously. Pharmacokinetic (PK) and pharmacodynamic (PD) data have not been publicly released for most B7-H4–targeted agents. To date, the only published PK result is that of the monoclonal antibody alsevalimab, with a half-life of 1–2 weeks.[23] Analysis of PK data from additional clinical trials will be crucial for understanding drug distribution, half-life, and exposure. Variations in PK and PD profiles may impact dosing strategies and patient tolerability.

Resistance to B7-H4–targeted agents may arise from various factors within the tumor microenvironment. Tumors may downregulate B7-H4 expression over time, reducing the effectiveness of therapies dependent on target antigen presentation. Upregulation of alternative immune checkpoints like PD-L1 can promote immune evasion, and tumor heterogeneity with variable B7-H4 expression across tumor regions limits the uniform efficacy of monotherapy.[12 ,30] Defects in apoptotic pathways or alterations in drug efflux mechanisms may also reduce the cytotoxic effects of ADCs, contributing to therapeutic resistance.[30] Combining B7-H4–targeted agents with PD-1, PD-L1, or PARP inhibitors may help overcome these resistance mechanisms by engaging complementary antitumor pathways.[12 ,30]

The efficacy of B7-H4–directed agents has the potential to be enhanced by incorporating exploratory biomarkers for patient selection in clinical trials. One promising candidate for a selective biomarker is B7-H4 protein expression, with elevated levels correlating with unfavorable prognosis across multiple malignancies, including breast, gastric, bladder, pancreatic, ovarian, renal cell carcinoma, hepatocellular carcinoma, and lung cancers.[5 ,9,31–36] Among the clinical trials we have summarized in this review, only the trials of alsevalimab and PF-07260437 required patients to have known B7-H4 expression for eligibility purposes. Although early-phase trial results on B7-H4–targeted agents are promising, more data are needed in B7-H4–positive cancers. Future studies should consider incorporating next-generation sequencing and B7-H4 immunohistochemistry (IHC) to stratify patients more effectively.

Combining B7-H4–targeted agents with additional agents could enhance efficacy and mitigate resistance, and it is a focus for several clinical trials without published data (Table 3). A preclinical study that evaluated the combination of felmetatug vedotin with an anti–PD-1 antibody in an immunocompetent murine tumor model enhanced antitumor activity. A subtherapeutic dose of felmetatug vedotin (1 mg/kg) in combination with anti-PD-1 mAb (0.3 mg/kg) resulted in 40% of mice having complete tumor regression, outperforming monotherapy with either agent. Additionally, 58% of mice receiving combination treatment were protected from tumor challenge, compared with 30% with maximum-dose monotherapy (3 mg/kg). Other in vivo models treated with felmetatug vedotin demonstrated upregulation of PD-L1, which is additional evidence that a PD1/PD-L1–directed combination strategy may overcome resistance to monotherapy.[12] A preclinical study that evaluated the combination of puxitatug samrotecan and a PARP1-selective inhibitor (AZD5305) in patient-derived xenograft (PDX) models also demonstrated improved efficacy. In high B7-H4 expressing PDX models, a suboptimal dose of puxitatug samrotecan (1.25 mg/kg) achieved 100% tumor growth inhibition (TGI) when combined with AZD5305, compared with 24.5% TGI with ADC monotherapy. In low B7-H4 expressing models, combination therapy resulted in 100% TGI, and monotherapy demonstrated modest activity with 32.9% TGI.[30] Additional agents under evaluation for combination therapy with B7-H4–targeted agents include PD1 inhibitor tislelizumab, PD-L1 inhibitor adebrelimab, VEGF monoclonal antibody bevacizumab, and bispecific antibody against TIGIT and PD1 relvegostomig. These agents have demonstrated promising antitumor activity with various other ADCs and mAbs with alternative targets. Preclinical studies evaluating these combinations with B7-H4–targeted agents have not yet been published, but they may have been performed and are, to date, undisclosed for proprietary reasons. New therapeutic strategies, including bispecific antibodies (T-cell engagers), are being developed to enhance the efficacy of B7-H4–targeted agents. These approaches leverage the ability to directly engage cytotoxic T cells, potentially overcoming the immunosuppressive tumor microenvironment associated with B7-H4 expression.[4] The development of such agents represents an important future direction, as they may offer improved efficacy over traditional monoclonal antibodies or ADCs.

B7-H4 shares structural similarities with B7-H3, another immune checkpoint molecule showing promising potential as a therapeutic target.[37] Both B7-H3 and B7-H4 are overexpressed in various tumors and contribute to immune evasion. Although B7-H3 tends to have a more ubiquitous expression across tumor types, B7-H4 is often more tumor-selective.[4] This selectivity could reduce toxicity risks and make B7-H4 an attractive target for bispecific antibodies (T-cell engagers).

This review has several limitations that impact the ability to draw comprehensive conclusions. One significant challenge is the limited understanding of B7-H4’s associated ligands and downstream signaling pathways, which complicates efforts to fully elucidate the role B7-H4 plays in immune regulation and tumor biology. Although B7-H4 acts as an inhibitory immune checkpoint by suppressing T-cell activation, the receptor(s) that mediate this interaction remain unidentified, hindering the development of rational combination strategies. Another challenge noted was the lack of standardized thresholds for B7-H4 expression, whether by IHC or RNA copy number. The absence of uniform cutoff values complicates both clinical trial design and future implementation in routine practice. The heterogeneous expression of B7-H4 across tumor types presents another barrier, as B7-H4 expression can vary widely, and the correlation between expression and treatment response is not yet fully established. Current trials have not publicly disclosed specific IHC scoring systems or RNA expression cutoffs, but future studies should aim to define these parameters to optimize patient selection. Additional limitations in this review include inconsistencies in the reporting of efficacy outcomes across studies, with variability in metrics such as objective response rates, stable disease, progressive disease, best percentage change in tumor size, and duration of treatment. This heterogeneity complicates cross-trial comparisons and limits the ability to draw definitive conclusions about clinical benefits. Similarly, the reporting of safety outcomes lacks uniformity, with differences in the reporting of treatment-emergent versus treatment-related adverse events (AEs), the grades of observed AEs, and the dose levels at which AEs and DLTs occur. Furthermore, the absence of comprehensive PK and PD data limits our understanding of drug exposure, distribution, and mechanisms of action, which are critical for optimizing dosing strategies and improving patient outcomes. These limitations underscore the need for more consistent and comprehensive reporting in the studies reviewed to better assess the clinical potential of B7-H4–targeted agents.

CONCLUSION

In summary, B7-H4–targeted agents represent a promising class of drugs that have demonstrated early antitumor activity in solid tumors, particularly breast, endometrial, and ovarian cancers. Although B7-H4–directed therapies show promise, several challenges remain, including a limited understanding of B7-H4 receptor(s), mechanisms of resistance, and the need for predictive biomarkers. ADCs, in combination with an immune checkpoint inhibitor, have shown promise preclinically and in early clinical results. Future studies should continue to evaluate safety and efficacy while optimizing combination therapies, particularly with PD-1/PD-L1 and PARP inhibitors.