Enoblituzumab (MGA271): An Investigational Anti-B7-H3 Monoclonal Antibody - Comprehensive Review

1. Introduction to Enoblituzumab (MGA271)

Enoblituzumab, also known by its investigational designation MGA271, is a humanized IgG1κ monoclonal antibody that has been developed as an immunotherapeutic agent targeting various forms of cancer.[1] As an investigational drug, it has been the subject of numerous clinical trials to evaluate its safety and efficacy.[3] The primary molecular target of enoblituzumab is B7-H3 (CD276), a transmembrane protein frequently overexpressed on the surface of a diverse array of tumor cells and often associated with a poor prognosis.[2] A distinguishing feature of enoblituzumab is its engineered fragment crystallizable (Fc) domain, a modification intended to significantly enhance its immune effector functions.[7] This Fc-optimization is a core element of its design by MacroGenics, aimed at improving its therapeutic potential compared to standard antibodies by augmenting its ability to trigger an immune response against cancer cells.

Key Identifiers and Properties:

Enoblituzumab is classified as a biotech therapeutic, specifically a monoclonal antibody.[3] Its Chemical Abstracts Service (CAS) Number is 1353485-38-7, and its DrugBank accession number is DB15017.[1] Alternative designations used in research and development include MGA271, MGA-271, TJ271, and TJ-271.[1] The Unique Ingredient Identifier (UNII) for enoblituzumab is M6030H73N9.[3]

Chemically and physically, enoblituzumab is a humanized IgG1κ monoclonal antibody with a molecular weight of approximately 146.1 kDa.[1] It is typically produced in Chinese Hamster Ovary (CHO) cells and purified using methods such as Protein A chromatography.[1] It is formulated as a liquid for administration and recommended for storage at -80°C.[1] Enoblituzumab is designed to be reactive with human B7-H3.[1]

Table 1: Enoblituzumab - Key Identifiers and Properties

Property	Details	Reference(s)
Generic Name	Enoblituzumab	User Query
Alternative Names	MGA271, MGA-271, TJ271, TJ-271	1
DrugBank ID	DB15017	User Query3
CAS Number	1353485-38-7	User Query1
UNII	M6030H73N9	3
Type	Biotech, Monoclonal Antibody	User Query3
Structure	Humanized IgG1κ, Fc-engineered	1
Molecular Weight	Approx. 146.1 kDa	1
Isotype	IgG1	1
Host for Production	CHO cells	1
Developer(s)	MacroGenics, I-MAB Biopharma (Greater China)	5

The consistent emphasis on the Fc-engineered nature of enoblituzumab throughout its documentation underscores a deliberate design strategy. Standard monoclonal antibodies possess Fc regions that interact with Fcγ receptors (FcγRs) on various immune cells, thereby mediating effector functions like antibody-dependent cellular cytotoxicity (ADCC). By modifying this Fc region, enoblituzumab was developed to exhibit enhanced binding to activating FcγRs, such as CD16A (FcγRIIIA), and concurrently reduced binding to inhibitory FcγRs, like CD32B (FcγRIIB).[8] This preferential binding profile is intended to amplify the antibody's capacity to destroy tumor cells via ADCC, a key component of its therapeutic hypothesis.

2. Mechanism of Action

The therapeutic activity of enoblituzumab is centered on its interaction with the B7-H3 protein and the subsequent engagement of the host immune system.

Target: B7-H3 (CD276) and its Role in Tumor Immune Evasion:

B7-H3, also known as CD276, is a type I transmembrane protein belonging to the B7 superfamily of immune checkpoint molecules.6 Unlike some other immune checkpoint proteins with restricted expression, B7-H3 is found to be overexpressed on a wide variety of solid tumor cells, cancer stem cells, and tumor-associated vasculature. Crucially, its expression on most normal tissues is minimal, which theoretically provides a favorable therapeutic window for targeted therapies.2 Elevated B7-H3 expression in tumors frequently correlates with more advanced disease stages, an increased likelihood of metastasis, and generally poorer patient prognosis.7

The functional role of B7-H3 in cancer is multifaceted. It is primarily implicated in immune evasion, contributing to the suppression of anti-tumor immune responses by inhibiting the activation and effector functions of immune cells, most notably T-lymphocytes and potentially Natural Killer (NK) cells.[6] B7-H3 is believed to exert its inhibitory effects by binding to a yet-to-be-definitively-identified receptor on T-cells.[7] Beyond its immunomodulatory functions, B7-H3 may also be involved in promoting tumor cell migration and invasion, conferring resistance to anti-cancer treatments, and influencing tumor metabolism.[8] The lack of definitive identification of the B7-H3 counter-receptor on T-cells represents a notable gap in fully understanding its precise signaling pathways and immunomodulatory mechanisms. This uncertainty could have implications for the comprehensive elucidation of enoblituzumab's effects on T-cell activity and for the development of highly specific pharmacodynamic biomarkers related to this aspect of its action.

Enoblituzumab's Binding and Fc-Engineered Enhancements:

Enoblituzumab is a humanized IgG1 monoclonal antibody engineered to bind with high affinity (dissociation constant, KD​≈7 nM) to human B7-H3.13 A cornerstone of its design is the modification of its Fc domain. This Fc engineering is specifically intended to augment its effector functions by:

• Increasing its binding affinity for the activating Fcγ receptor CD16A (FcγRIIIA), which is expressed on NK cells, macrophages, and other myeloid cells. This enhanced binding includes the low-affinity F158V allotypic variant of CD16A.[8]
• Decreasing its binding affinity for the inhibitory Fcγ receptor CD32B (FcγRIIB), which can dampen immune cell activation.[9] These alterations in FcγR binding are designed to significantly potentiate ADCC, a process whereby antibody-coated target cells are recognized and lysed by effector immune cells.[4]

Impact on Innate and Adaptive Immune Cells (T-cell and NK cell engagement):

The mechanism of enoblituzumab involves a multi-pronged approach to immune activation:

• Primary Mechanism: Antibody-Dependent Cellular Cytotoxicity (ADCC): The Fc-optimization of enoblituzumab is central to its primary proposed mechanism of action. By enhancing engagement with activating FcγRs on innate immune cells, particularly NK cells and macrophages, enoblituzumab aims to trigger more efficient lysis of B7-H3-expressing tumor cells.[7] This proactive cytotoxic mechanism distinguishes enoblituzumab from many checkpoint inhibitors that primarily rely on releasing pre-existing T-cell responses.
• T-cell Modulation: In addition to direct ADCC, enoblituzumab is hypothesized to modulate T-cell function. By binding to B7-H3 on tumor cells, it may block an inhibitory signal to T-cells, thereby relieving T-cell suppression and enhancing the activity of cytotoxic T lymphocytes (CTLs).[6] Clinical and preclinical observations support this, with evidence suggesting enoblituzumab can lead to increased peripheral T-cell clonality and abundance, as well as enhanced local T-cell infiltration into tumors, such as in prostate cancer models.[2]
• NK Cell Activation: In vitro studies have indicated that enoblituzumab-mediated ADCC is associated with increased interferon-gamma (IFN-γ) expression and upregulation of Programmed Death-Ligand 1 (PD-L1) on NK cells.[14] Furthermore, combining enoblituzumab with an anti-PD-1 antibody (like pembrolizumab) can further augment IFN-γ secretion by both NK cells and CD8+ T-cells, suggesting a synergistic potential.[12]
• Coordinate Engagement of Innate and Adaptive Immunity: The overarching therapeutic strategy, especially when enoblituzumab is used in combination regimens (e.g., with anti-PD-1 antibodies), is to simultaneously engage both the innate immune system (primarily through enhanced ADCC) and the adaptive immune system (through T-cell de-repression and activation). This dual engagement is anticipated to yield a more comprehensive and potent anti-tumor immune response than either modality alone.[8] Translational research conducted by I-Mab Biopharma has provided further support for this dual mechanism, confirming the immunosuppressive role of B7-H3 and demonstrating enoblituzumab's capacity to promote an immunoregulatory shift. This includes the activation of cytolytic T cells and NK cells, the reinvigoration of previously exhausted immune cells, and the suppression of M2-polarized (pro-tumor) myeloid cells.[18] This combination of direct tumor cell killing via ADCC and the broader modulation of the immune microenvironment represents a sophisticated approach to cancer immunotherapy.

3. Preclinical Development and Rationale

The progression of enoblituzumab into clinical trials was underpinned by a robust preclinical rationale, primarily based on the expression pattern of its target, B7-H3, and its demonstrated anti-tumor activity in various non-clinical models.

Expression Profile of B7-H3:

A critical factor supporting the development of enoblituzumab was the observed differential expression of B7-H3. Immunohistochemical (IHC) analyses, often utilizing the parental antibody from which enoblituzumab was derived, consistently showed that B7-H3 expression is limited in most normal, healthy tissues but is significantly upregulated in a wide array of human cancers.16 This tumor-associated expression pattern suggested that B7-H3 could serve as a selective target, allowing for therapeutic intervention with a potentially favorable safety margin. High levels of B7-H3 expression were reported in various pediatric solid tumors, including neuroblastoma, rhabdomyosarcoma, osteosarcoma, Wilms tumor, Ewing's sarcoma, and desmoplastic small round cell tumor, further broadening its potential applicability.16

Anti-tumor Activity in Preclinical Models:

Enoblituzumab (MGA271) demonstrated significant anti-tumor effects in preclinical settings:

• In vitro, it was shown to mediate potent ADCC against a variety of B7-H3-positive solid tumor cell lines.[4]
• In vivo, enoblituzumab significantly inhibited the growth of B7-H3-expressing renal and bladder cancer xenografts in animal models.[4]
• Preclinical work by I-Mab Biopharma further confirmed enoblituzumab's ability to induce tumor cell killing in vitro, using the B7-H3-expressing ovarian cancer cell line ES-2 as a model.[18]
• Importantly, preclinical studies exploring combination therapies indicated that the concurrent targeting of B7-H3 (with enoblituzumab) and the PD-1/PD-L1 axis could result in greater anti-tumor activity than that achieved with either agent administered alone.[8] This provided a strong basis for investigating such combinations in clinical trials.

The broad expression of B7-H3 across diverse tumor histologies, as identified in preclinical assessments [13], was a key factor suggesting that enoblituzumab could possess wide-ranging applicability. This is reflected in the variety of cancer types, including prostate cancer, bladder cancer, melanoma, head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), and various pediatric malignancies, that were subsequently investigated in early-phase clinical trials. Had B7-H3 expression been confined to only one or two tumor types, the scope of the clinical development program for enoblituzumab would likely have been considerably more restricted.

Rationale for Clinical Investigation:

The rationale for advancing enoblituzumab into clinical trials was compelling, based on several factors:

• The widespread overexpression of B7-H3 in multiple tumor types and its established correlation with poor clinical outcomes (e.g., advanced disease, metastasis) highlighted B7-H3 as an attractive and clinically relevant therapeutic target.[6]
• The unique Fc-engineered design of enoblituzumab, aimed at maximizing ADCC, offered a potentially more potent mechanism for eliminating tumor cells compared to standard antibodies.
• The additional potential for enoblituzumab to modulate T-cell function by blocking B7-H3-mediated immune suppression provided a dual mechanism of action. Together, these characteristics provided a strong scientific basis for evaluating enoblituzumab in human clinical trials, both as a monotherapy and in combination with other immunotherapeutic agents, such as checkpoint inhibitors.[2]

4. Clinical Development Program

Enoblituzumab has undergone evaluation in a series of Phase 1 and Phase 2 clinical trials, assessing its utility as a monotherapy and in combination with other immuno-oncology agents, across various solid tumors in both adult and pediatric patient populations. The clinical journey of enoblituzumab reflects an initial period of promise followed by significant challenges, particularly in later-stage development.

Table 2: Overview of Key Clinical Trials for Enoblituzumab

NCT ID	Phase	Indication(s) / Patient Population	Treatment Regimen	Key Objectives	Status (as per latest snippets)	Key Published Outcomes/References (Snippet IDs)
NCT02982941	1	Children & young adults (1-35 yrs) with relapsed/refractory B7-H3-expressing solid tumors (neuroblastoma, rhabdomyosarcoma, osteosarcoma, Ewing's, Wilms, DSRCT, others)	Enoblituzumab IV weekly (starting 10 mg/kg, dose escalation)	Safety, tolerability, PK, PD, immunogenicity, preliminary anti-tumor activity, MTD	Complete 19	Design/objectives published 16; Detailed results largely unpublished 16
NCT01391143	1	Adults with refractory B7-H3+ neoplasms or tumors with B7-H3+ vasculature (melanoma, prostate, bladder, HNSCC, RCC, TNBC, lung)	Enoblituzumab monotherapy (0.01-15 mg/kg IV weekly)	Safety, tolerability, PK, PD, anti-tumor activity, MTD	Completed (expansion ongoing as of 2015) 9	Interim safety, PK, PD, efficacy 2
NCT02923180	2	Adults with high-risk localized prostate cancer (neoadjuvant)	Enoblituzumab (15 mg/kg IV weekly x 6 doses) prior to prostatectomy	Safety, PSA0 at 1 year post-prostatectomy, PD	Completed 20	Safety, efficacy (PSA0), PD results published 20
NCT02475213	1/2	Adults with advanced B7-H3-expressing solid tumors (NSCLC, HNSCC, urothelial, melanoma; CPI-naïve & post-CPI)	Enoblituzumab (3-15 mg/kg weekly or Q3W) + Pembrolizumab (2 mg/kg Q3W)	Safety, MTD/RP2D, anti-tumor activity	Completed (data published) 22	Safety, PK, PD, efficacy results published 8
NCT04634825	2	Adults with 1st line recurrent/metastatic SCCHN	Enoblituzumab (15 mg/kg Q3W) + Retifanlimab (375 mg Q3W) OR Enoblituzumab (15 mg/kg Q3W) + Tebotelimab (600 mg Q3W)	Efficacy, safety	Terminated/Closed Early (July 2022) 25	Study closure due to safety (hemorrhagic events) 12
NCT05338580	2	Adults with solid tumors (NSCLC, urothelial, others; China)	Enoblituzumab + Pembrolizumab	Efficacy, safety	Withdrawn (April 2024) 5	Trial initiated by I-Mab, later withdrawn 11
NCT02381314	1	Adults with B7-H3-expressing HNSCC and other solid tumors	Enoblituzumab + Ipilimumab	Safety, MTD, preliminary efficacy	Status not detailed, results pending in one source 4	Mentioned as ongoing/pending 4
NCT05708924	1	Adults with recurrent ovarian, fallopian tube, primary peritoneal cancer	Enoblituzumab + FT538	Safety, efficacy	Terminated 27	Reason for termination not specified in snippets

Focus on NCT02982941: Enoblituzumab (MGA271) in Children with B7-H3-expressing Solid Tumors

This clinical trial (NCT02982941, CP-MGA271-04) was a Phase 1, open-label, dose-escalation, and cohort expansion study specifically designed to evaluate enoblituzumab in pediatric and young adult patients.[16]

• Study Design, Objectives, and Endpoints: The primary objectives were to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary anti-tumor activity of enoblituzumab. A key goal was to determine the Maximum Tolerated Dose (MTD).[16] Enoblituzumab was administered intravenously (IV) on a weekly schedule, with doses starting at 10 mg/kg in escalating cohorts using a 3+3 design. Treatment could continue for up to 96 doses, approximately two years.[16] Tumor response was first assessed at 8 weeks, using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) for patient management.[16]
• Patient Population and Eligibility Criteria: The trial enrolled patients aged 1 to 35 years.[19] During the dose-escalation phase, patients with relapsed or refractory malignant solid tumors of any histology for which no standard curative therapy was available were eligible.[19] The cohort expansion phase focused on specific histologies: neuroblastoma (both measurable and non-measurable disease), rhabdomyosarcoma, osteosarcoma, Ewing's sarcoma/primitive neuroectodermal tumor (PNET), Wilms tumor, desmoplastic small round cell tumor (DSRCT), or other solid tumors confirmed to be B7-H3 positive.[16] A critical inclusion criterion was the demonstration of B7-H3 expression by IHC, defined as 2+ or greater staining intensity on at least 10% of tumor cells or on ≥25% of the tumor vasculature.[19] Patients were required to have measurable disease as per RECIST v1.1 (with an exception for non-measurable neuroblastoma), an adequate performance status (Karnofsky Performance Status ≥70 for patients ≥16 years or Lansky Performance Score ≥70 for patients <16 years), and satisfactory laboratory parameters indicating adequate organ reserve.[19] Key exclusion criteria included symptomatic central nervous system (CNS) disease (unless previously treated and currently asymptomatic), a history of known or suspected autoimmune disease (with certain specified exceptions), prior allogeneic bone marrow/stem-cell or solid organ transplantation, recent systemic chemotherapy, investigational therapy, or radiation therapy, significant cardiovascular disease, active systemic infections, known HIV positivity, or active Hepatitis B or C infection.[19]
• Safety, Tolerability, and Efficacy Data: Despite the trial being listed as "complete" on ClinicalTrials.gov (as per NCI records) [19], specific, detailed peer-reviewed published results regarding safety outcomes, tolerability, objective response rates (ORR), and comprehensive PK/PD findings from NCT02982941 are notably absent in the available information.[16] One source indicates that the Phase 1 study involving pediatric patients and MGA271 concluded in May 2019, but states that the "final findings have not been made available to the public".[16] Another account mentions that apart from a 2017 abstract confirming the initiation of enrollment, "no updates or results have been [published]".[16] While a general statement suggests enoblituzumab "has been shown to reduce the growth rates of cancer" in children and references NCT02982941 in the context of neuroblastoma, rhabdomyosarcoma, and osteosarcoma [4], this claim is not directly substantiated with specific data from this trial within the provided documents. This lack of detailed, publicly available results from a completed pediatric trial represents a significant information gap, particularly given the trial's relevance to the initial query.

Other Significant Clinical Trials:

• NCT01391143 (Monotherapy in B7-H3+ Neoplasms): This Phase 1 dose-escalation (0.01-15 mg/kg) and cohort expansion study in adults with refractory B7-H3-expressing tumors provided early insights into enoblituzumab's profile.[9]
• Safety: Enoblituzumab was well tolerated; no dose-limiting toxicities (DLTs) were observed, and the MTD was not reached up to 15 mg/kg. Common treatment-related adverse events (TRAEs) included fatigue (30%), infusion-related reactions (IRR) (26%), and nausea (19%). Grade 3/4 drug-related AEs were infrequent (6%), and no discontinuations occurred due to drug-related AEs.[9]
• PK: The pharmacokinetic profile was linear.[9]
• PD: Pharmacodynamic assessments showed modulation of lymphocyte phenotypes and an increase in T-cell clonality in peripheral blood, suggesting immune activation.[2]
• Efficacy: Preliminary anti-tumor activity was observed, with disease stabilization (>12 weeks) and tumor shrinkage (ranging from 2% to 69%) reported across several tumor types, including in heavily pre-treated patients with melanoma, prostate cancer, and bladder cancer.[2]
• NCT02923180 (Neoadjuvant in Localized Prostate Cancer): This Phase 2 trial evaluated enoblituzumab (15 mg/kg IV weekly for 6 doses) administered prior to radical prostatectomy in 32 men with high-risk localized prostate cancer.[7]
• Safety: The primary safety endpoint was met, with no unexpected surgical or medical complications. Grade 3 AEs occurred in 12% of patients (including IRR with hypotension, asymptomatic amylase/lipase elevation, rash, and perimyocarditis with pericardial effusion); no Grade 4 AEs or treatment-related deaths were reported.[20]
• Efficacy: The co-primary endpoint of an undetectable PSA level (PSA0 < 0.1 ng/mL) at 1 year post-prostatectomy was achieved in 66% of patients (95% CI 47-81%).[20]
• PD: Enoblituzumab was confirmed to penetrate prostate tissue and bind to B7-H3. Post-treatment analyses revealed broad immune-stimulatory activity within the tumor microenvironment (TME), including increased markers of cytotoxicity (granzyme B, OX40L) and infiltration of various immune cells (CD8+ T cells, granulocytes, leukocytes, APCs). Systemic cytokine changes also indicated immune modulation.[21]
• NCT02475213 (Combination with Pembrolizumab in Advanced Solid Tumors): This Phase 1/2 study assessed enoblituzumab (3–15 mg/kg weekly or Q3W) combined with pembrolizumab (2 mg/kg Q3W).[8]
• RP2D: Enoblituzumab 15 mg/kg Q3W plus pembrolizumab 2 mg/kg Q3W was selected.[14]
• Safety: The combination had an acceptable safety profile. TRAEs occurred in 87.2% of patients (Grade ≥3 in 28.6%). Common TRAEs were IRRs (54.1%) and fatigue (27.8%). One treatment-related death due to pneumonitis was reported.[8]
• Efficacy (CPI-naïve patients): In HNSCC, the ORR was 33.3% (6/18), with a disease control rate (DCR) of 61.1%. In NSCLC (PD-L1 <1%), the ORR was 35.7% (5/14), with a DCR of 92.8%.[8] Responses in CPI-experienced patients were limited (ORR 5.9% in urothelial cancer, 7.7% in melanoma).[14]
• NCT04634825 (Combination with Retifanlimab or Tebotelimab in R/M SCCHN): This Phase 2 trial for first-line R/M SCCHN was notably closed early in July 2022.[12] The decision followed an internal safety review that identified seven fatalities potentially linked to hemorrhagic events across the study arms.[25] This event marked a significant safety concern for the program.
• NCT05338580 (I-Mab Biopharma - Basket trial in China): I-Mab Biopharma, which held rights for Greater China, initiated this Phase 2 basket trial combining enoblituzumab with pembrolizumab in solid tumors.[11] However, the trial was withdrawn in April 2024 due to adjustments in the company's development strategy.[5]
• NCT05708924 (Combination with FT538 in Ovarian Cancer): This Phase 1 trial was terminated.[27] The reasons for termination were not specified in the provided documents.

The clinical development of enoblituzumab shows a path of initial promise, particularly in early-phase monotherapy and specific combination settings like neoadjuvant prostate cancer and CPI-naïve HNSCC/NSCLC. However, the program encountered a major setback with the early termination of the NCT04634825 trial due to fatal hemorrhagic events, a severe safety signal that likely influenced subsequent development decisions. Furthermore, the strategic shifts by both MacroGenics and I-Mab Biopharma, moving away from the naked antibody or withdrawing trials, suggest a complex and challenging development landscape for enoblituzumab in its current formulation. MacroGenics, for instance, appears to be leveraging the B7-H3 targeting moiety of enoblituzumab in next-generation constructs like antibody-drug conjugates (ADCs), such as MGC026, which shares enoblituzumab's variable domain.[31] This pivot suggests a belief that alternative delivery mechanisms or payloads might offer a better therapeutic index for the B7-H3 target.

5. Pharmacokinetics (PK) of Enoblituzumab

The pharmacokinetic profile of enoblituzumab has been characterized in Phase 1 clinical trials, both as a monotherapy and in combination with other agents.

General Characteristics:

Enoblituzumab exhibited linear pharmacokinetics in the Phase 1 monotherapy study (NCT01391143) across the dose ranges tested.9 In the combination study with pembrolizumab (NCT02475213), which involved 130 patients, the maximum observed serum concentration (Cmax​) of enoblituzumab increased in a manner proportional to the dose. The systemic exposure, measured by the area under the serum concentration–time curve (AUC), increased slightly more than proportionally to the dose over the range of 3–15 mg/kg.14

Absorption:

Enoblituzumab is administered via intravenous (IV) infusion.9 For drugs administered intravenously, bioavailability is considered to be 100% as the entire dose directly enters systemic circulation.

Distribution:

In the combination study with pembrolizumab, the volume of distribution at steady state (Vss​) was reported to be not dose-related after the first dose.14 Specific quantitative values for Vss​ are not provided in the available documents. As a monoclonal antibody, enoblituzumab is expected to primarily distribute within the vascular and interstitial spaces.

Metabolism:

Being a protein-based therapeutic (monoclonal antibody), enoblituzumab is anticipated to undergo metabolism through general protein catabolic pathways. This involves degradation into smaller peptides and constituent amino acids, which are then reutilized by the body or excreted.3 Specific cytochrome P450 (CYP) enzyme pathways, which are typical for small molecule drug metabolism, are not expected to be the primary routes for enoblituzumab metabolism. Detailed metabolic pathways specific to enoblituzumab are not elaborated in the provided documents.

Elimination (Clearance and Half-life):

The clearance of enoblituzumab was not found to be dose-related after the initial dose in the combination study with pembrolizumab.14

The terminal elimination half-life (t1/2​) of enoblituzumab has been reported with some variation across different study reports or presentations. An earlier presentation from the SITC 2015 meeting concerning the monotherapy trial (NCT01391143) indicated a terminal half-life of approximately 3 weeks.13

More detailed pharmacokinetic data from the subsequent combination study with pembrolizumab (NCT02475213) reported that the t1/2​ of enoblituzumab was approximately 12 days following multiple doses. It was also noted that trough serum concentrations for the 15 mg/kg dose continued to increase over eight cycles, approaching a plateau by week 33. This observation suggests that the effective half-life at this higher dose, after multiple administrations, might be longer than 12 days, or that steady state was achieved more slowly.14 This apparent evolution in reported half-life values could be attributed to differences in study populations, the assays used for quantification, variations in dosing schedules, the context of monotherapy versus combination therapy, or simply the maturation of pharmacokinetic understanding as more data became available from larger patient cohorts.

Dose Proportionality:

As mentioned, the Cmax​ of enoblituzumab increased dose-proportionally, while the AUC showed a trend of increasing slightly more than dose-proportionally within the 3-15 mg/kg dose range evaluated in the combination study.14

6. Pharmacodynamics (PD) of Enoblituzumab

Pharmacodynamic studies have been integral to understanding enoblituzumab's biological effects, confirming target engagement and characterizing its impact on the immune system both locally within the tumor microenvironment and systemically.

Target Engagement:

Enoblituzumab effectively binds to its designated target, B7-H3, which is expressed on tumor cells and cells within the tumor vasculature.2 This target engagement was directly confirmed in the neoadjuvant prostate cancer trial (NCT02923180), where post-prostatectomy analysis of tissue samples showed that enoblituzumab had successfully penetrated the prostate gland and bound to B7-H3 in 28 out of 32 (88%) patients.21

Immune Cell Modulation in Tumor Microenvironment (TME):

Treatment with enoblituzumab has been shown to induce significant changes within the TME:

• In the neoadjuvant prostate cancer study (NCT02923180), analysis of prostatectomy specimens following enoblituzumab treatment revealed evidence of broad immune-stimulatory activity. This included increased expression of markers associated with cytotoxicity, such as granzyme B and OX40L. Furthermore, there was an upregulation in the presence of granulocytes (CD66B-positive), leukocytes (CD45-positive), effector T cells (CD8-positive), and monocytic antigen-presenting cells (HLA-DR-positive, CD163-positive). Notably, a 1.8-fold increase in tumor-infiltrating CD8+ T cells was observed.[21]
• Interestingly, the same study also reported an upregulation of inhibitory markers within the TME post-treatment. These included PD-L1, FoxP3 (a marker for regulatory T cells), and B7-H3 itself.[21] This upregulation of inhibitory molecules following an initial immune activation is a critical pharmacodynamic observation. It suggests that while enoblituzumab can effectively stimulate an anti-tumor immune response, the tumor and its microenvironment may adapt by upregulating these counter-regulatory pathways. Such adaptive resistance mechanisms are common in immunotherapy and provide a strong rationale for combining B7-H3 targeting with agents that block these newly upregulated inhibitory signals, such as PD-1/PD-L1 inhibitors.

Systemic Immune Modulation:

Enoblituzumab's effects extend beyond the local TME to systemic immune parameters:

• T-cell Repertoire: Data from the Phase 1 monotherapy trial (NCT01391143) indicated that enoblituzumab treatment led to increases in T-cell receptor (TCR) clonality and the abundance of specific T-cell clones in the peripheral blood of patients.[2] In the neoadjuvant prostate cancer trial (NCT02923180), an exploratory analysis found a correlation between clinical outcome and T-cell dynamics: patients whose peripherally expanded T-cell clones were also detected within the tumor tissue were more likely to achieve an undetectable PSA (PSA0) at one year.[21] This finding, while based on a small number of patients, hints that the trafficking of specific, peripherally-expanded T-cell clones into the tumor might be a relevant pharmacodynamic marker of response.
• Cytokine Changes:
• Pharmacodynamic testing in the Phase 1 monotherapy study included the assessment of serum cytokines, although specific changes were not detailed in the interim reports.[9]
• In the neoadjuvant prostate cancer trial, post-treatment blood samples showed increased systemic levels of pro-inflammatory and immune-activating cytokines such as IL-2, IL-36b, and IL-17, as well as soluble 4-1BB (CD137), a co-stimulatory molecule. Conversely, levels of IL-15 and IL-6 were observed to decrease post-treatment.[21]
• NK Cell Priming: In vitro studies demonstrated that enoblituzumab-mediated ADCC was associated with increased IFN-γ production and PD-L1 upregulation on NK cells. Co-administration of pembrolizumab (an anti-PD-1 antibody) was shown to further enhance IFN-γ secretion by both NK cells and CD8+ T-cells, highlighting a potential for synergistic immune activation.[12]

Antibody-Dependent Cellular Cytotoxicity (ADCC):

ADCC is considered a primary mechanism of action for enoblituzumab, largely attributed to its Fc-engineered domain designed to enhance interactions with activating Fcγ receptors on effector cells.4 Research conducted by I-Mab Biopharma further corroborated that enoblituzumab effectively mediates ADCC, leading to the killing of cancer cells.11

7. Safety and Tolerability Profile

The safety and tolerability of enoblituzumab have been evaluated in various clinical trials, both as a monotherapy and in combination with checkpoint inhibitors. While generally manageable in early studies, significant safety concerns emerged in a later trial.

Table 3: Summary of Safety Profile of Enoblituzumab (Monotherapy and Key Combinations)

Adverse Event Category	Specific AE	Monotherapy (NCT01391143)	Monotherapy (NCT02923180 - Prostate)	Pembrolizumab Combo (NCT02475213)	Retifanlimab/Tebotelimab Combo (NCT04634825 - HNSCC)
Most Common TRAEs (Any Grade)	Fatigue	30%	72%	27.8%	Data not detailed prior to closure
	Infusion-Related Reaction (IRR)	26%	22% (G1/2)	54.1%	Data not detailed prior to closure
	Nausea	19%	38% (GI symptoms)	9.0%	Data not detailed prior to closure
	Chills	17%	38% (Flu-like/cold)	5.3%	Data not detailed prior to closure
	Vomiting	13%	38% (GI symptoms)	Not in top list	Data not detailed prior to closure
	Rash	Not in top list	9% (maculopapular)	10.5%	Data not detailed prior to closure
Grade ≥3 TRAEs	Any	6%	12%	28.6%	Not detailed, but led to trial closure
	IRR	Not specified	3% (with hypotension)	6.8%	Not detailed
	Increased Lipase	Not specified	3% (asymptomatic)	6.0%	Not detailed
	Perimyocarditis	Not applicable	3% (one patient)	Not reported	Not detailed
	Hemorrhagic Events	Not reported	Not reported	Not reported	7 Fatalities (Potentially Linked)
Immune-Related AEs (irAEs)	Pneumonitis	No severe irAEs	Not observed	3.8% (1.5% G≥3, 1 death)	Not detailed
	Rash	No severe irAEs	Not specified as irAE	11.3%	Not detailed
	Thyroid events	No severe irAEs	Not specified as irAE	7.5%	Not detailed
Discontinuations due to TRAEs	Any	0%	Not specified (all completed treatment)	9.8%	Trial closed
Treatment-Related Deaths	Any	0	0	1 (Pneumonitis)	7 (Potentially Hemorrhagic)

Monotherapy (NCT01391143, NCT02923180):

In early Phase 1 studies (NCT01391143) involving adults with various tumors, enoblituzumab monotherapy was generally well-tolerated.2 The MTD was not defined up to doses of 15 mg/kg. The most frequently reported TRAEs included fatigue (30%), IRR (26%), nausea (19%), chills (17%), and vomiting (13%). Grade 3/4 drug-related AEs were noted in 6% of patients, and importantly, no patients discontinued treatment due to drug-related AEs. No severe immune-related AEs were reported in these initial evaluations.2

In the neoadjuvant prostate cancer trial (NCT02923180), the primary safety endpoint was met, with no unexpected surgical or medical complications. Grade 3 AEs occurred in 12% of patients; these included one case of IRR with hypotension, one of asymptomatic amylase/lipase elevation, one maculopapular rash, and one instance of perimyocarditis with pericardial effusion (which resolved). No Grade 4 AEs or treatment-related deaths occurred.20 Infusion-related reactions appear to be a consistent adverse event associated with enoblituzumab, observed across both monotherapy and combination studies.2 While often mild to moderate and manageable, their frequent occurrence (e.g., 22-26% in monotherapy, 54.1% in the pembrolizumab combination) is noteworthy. This may be an intrinsic consequence of the antibody's Fc-engineering, which is designed to enhance interactions with Fcγ receptors, potentially leading to greater cytokine release upon initial engagement.

Combination with Pembrolizumab (NCT02475213):

The combination of enoblituzumab with pembrolizumab demonstrated an acceptable safety profile, and the MTD of enoblituzumab was not reached when co-administered with pembrolizumab at 2 mg/kg.8 TRAEs were reported in 87.2% of patients, with Grade ≥3 TRAEs occurring in 28.6%. The most common TRAEs were IRRs (54.1%) and fatigue (27.8%). Notable Grade ≥3 TRAEs included IRRs (6.8%) and increased lipase (6.0%). There was one treatment-related death attributed to immunotherapy-induced pneumonitis.8 The rate and types of irAEs (e.g., rash, thyroid events, arthralgia) were generally comparable to those observed with anti-PD-1 monotherapy.8

Combination with Retifanlimab or Tebotelimab (NCT04634825 in R/M SCCHN):

A critical turning point in the safety assessment of enoblituzumab came with the Phase 2 CP-MGA271-06 trial (NCT04634825). This study, evaluating enoblituzumab in combination with either retifanlimab (anti-PD-1) or tebotelimab (anti-PD-1/LAG-3 bispecific) in first-line R/M SCCHN, was closed early in July 2022 due to significant safety concerns.25 An internal review of safety data identified seven fatalities that were potentially linked to hemorrhagic events across the two arms of the trial.25 This emergence of severe, unexpected toxicity in the form of fatal hemorrhagic events was not a prominent feature in earlier trials and represented a major safety signal that likely had a profound impact on the subsequent development trajectory of enoblituzumab as a naked antibody. The specific reasons for this toxicity in this particular setting (e.g., patient population, specific combination agents, or unforeseen interactions) are not fully elucidated by the provided documents but underscore the complexities of combination immunotherapy.

Pediatric Population (NCT02982941):

Detailed safety and tolerability data from the completed pediatric trial (NCT02982941) are not available in the provided documents.16 This remains an area where published information is needed for a comprehensive safety assessment in children and young adults.

8. Clinical Efficacy Across Indications

The clinical efficacy of enoblituzumab has been varied, showing promise in some early-phase settings and specific patient populations, but with limitations in others.

Table 4: Summary of Efficacy of Enoblituzumab (Key Trials and Indications)

Trial ID	Indication	Patient Population	Treatment Regimen	Key Efficacy Endpoint(s)	Reported Results (95% CI if available)	Snippet Reference(s)
NCT01391143	Various Solid Tumors	Heavily pre-treated adults	Enoblituzumab Monotherapy	Tumor shrinkage, Disease stabilization	Disease stabilization (>12 wks), Tumor shrinkage (2-69%) in melanoma, prostate, bladder	2
NCT02923180	Localized Prostate Cancer	Neoadjuvant, high-risk adults	Enoblituzumab Monotherapy	PSA0 at 1 year	66% (47-81%)	20
NCT02475213	HNSCC	CPI-naïve, post-platinum adults	Enoblituzumab + Pembrolizumab	ORR, DCR, DOR, PFS	ORR: 33.3% (1 CR, 5 PRs); DCR: 61.1%; Median DOR: Not Reached; 6-mo PFS: 42.1%	8
NCT02475213	NSCLC (PD-L1 <1%)	CPI-naïve adults	Enoblituzumab + Pembrolizumab	ORR, DCR, DOR, PFS	ORR: 35.7% (all PRs); DCR: 92.8%; Median DOR: 8.3 mo; 6-mo PFS: 43.3%	8
NCT02475213	Urothelial Cancer	Post-CPI adults	Enoblituzumab + Pembrolizumab	ORR	5.9%	14
NCT02475213	Melanoma	Post-CPI adults	Enoblituzumab + Pembrolizumab	ORR	7.7%	14
NCT02982941	Pediatric Solid Tumors	Relapsed/refractory, B7-H3+	Enoblituzumab Monotherapy	ORR, DOR, PFS	Detailed results not published. General statement: "shown to reduce growth rates" 4, but lacks specific trial data.	4

Monotherapy (NCT01391143):

In the Phase 1 monotherapy study involving heavily pre-treated adult patients with various B7-H3-expressing tumors, enoblituzumab demonstrated anti-tumor activity. This was characterized by disease stabilization lasting over 12 weeks and instances of tumor shrinkage ranging from 2% to 69% in patients with melanoma, prostate cancer, and bladder cancer.2 Specific ORR figures for the overall study population were not detailed in the available interim reports.

Neoadjuvant Prostate Cancer (NCT02923180):

In men with high-risk localized prostate cancer receiving enoblituzumab prior to surgery, a significant proportion achieved an undetectable PSA level (PSA0 < 0.1 ng/mL) one year after prostatectomy. The PSA0 rate was 66% (95% CI 47-81%), suggesting potential clinical benefit in this setting.20

Combination with Pembrolizumab (NCT02475213):

This combination showed encouraging activity, particularly in checkpoint inhibitor (CPI)-naïve populations:

• CPI-Naïve HNSCC (post-platinum): The ORR was 33.3% (6 out of 18 patients), which included one complete response (CR) and five partial responses (PRs). The DCR was 61.1%. The median duration of response (DOR) was not reached at the time of reporting, and the 6-month progression-free survival (PFS) rate was 42.1%.[8] These results were considered to benchmark favorably against historical data for anti-PD-1 monotherapy in similar populations.[8]
• CPI-Naïve NSCLC (PD-L1 <1%): In this cohort, the ORR was 35.7% (5 out of 14 patients), all of whom achieved PRs. The DCR was notably high at 92.8%. The median DOR was 8.3 months, and the 6-month PFS rate was 43.3%.[8] The efficacy in these CPI-naïve groups suggests that the combination of enoblituzumab and pembrolizumab might be more effective in immune environments that have not been previously exposed to, and potentially developed resistance to, checkpoint inhibition.
• Post-CPI Populations: In contrast, limited responses were observed in patients who had previously received CPI therapy. The ORR was 5.9% in the post-CPI urothelial cancer cohort and 7.7% in the post-CPI melanoma cohort.[14] This disparity implies that prior CPI exposure might induce resistance mechanisms that also diminish the efficacy of the enoblituzumab-pembrolizumab combination, or that these populations are inherently more refractory.

Pediatric Solid Tumors (NCT02982941):

Despite B7-H3 being highly expressed in many pediatric solid tumors 16 and the completion of the dedicated pediatric Phase 1 trial (NCT02982941) 19, detailed, peer-reviewed efficacy results (such as ORR, DOR, PFS) are conspicuously absent from the provided documents.16 A general assertion that enoblituzumab "has been shown to reduce the growth rates of cancer" in children 4 is not substantiated with specific data from this trial in the available information. This lack of concrete efficacy data from the pediatric study is a significant unknown, particularly given the initial focus on this trial in the user's query. The actual clinical benefit of enoblituzumab in children with B7-H3-expressing tumors remains unconfirmed by the provided materials.

9. Regulatory Status and Future Outlook

Enoblituzumab remains an investigational agent and has not received marketing approval from major regulatory bodies such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for any indication, based on the information available.[3]

Orphan Drug Designations:

According to AdisInsight (data last updated April 2024), enoblituzumab, as developed by MacroGenics for its cancer indications, does not currently hold orphan drug status.5 Other provided documents discuss orphan drug designation processes or designations for different pharmaceutical agents and are not directly applicable to enoblituzumab's oncology development program.34

Developer Updates and Strategic Shifts:

The development trajectory of enoblituzumab as a naked monoclonal antibody has been significantly impacted by strategic decisions from its developers:

• MacroGenics (Originator):
• As of April 2024, MacroGenics has discontinued the development of enoblituzumab for a multitude of indications, including bladder cancer, fallopian tube cancer, head and neck cancer, malignant melanoma, non-small cell lung cancer, ovarian cancer, peritoneal cancer, solid tumors, squamous cell cancer, and urogenital cancer.[5]
• A pivotal event was the early closure of the Phase 2 CP-MGA271-06 trial (NCT04634825) in HNSCC in July 2022. This decision was made due to safety concerns, specifically seven fatalities potentially linked to hemorrhagic events observed in the study.[25]
• Recent pipeline updates from MacroGenics for Q4 2024 and Q1 2025 do not feature enoblituzumab (MGA271) as a prominently ongoing or prioritized program in its naked antibody format.[31] Instead, the company's focus for targeting B7-H3 appears to have transitioned towards antibody-drug conjugates (ADCs). Notably, MGC026, an ADC, utilizes the same B7-H3 binding variable domain as enoblituzumab but is conjugated to a topoisomerase I inhibitor payload, suggesting an effort to leverage the targeting specificity in a different therapeutic modality.[31] This strategic pivot from a naked monoclonal antibody to an ADC for B7-H3 targeting strongly implies a determination that ADCs might offer an improved therapeutic index or enhanced efficacy for this particular target. The discontinuation of multiple enoblituzumab trials, coupled with the serious adverse events in the HNSCC trial, likely prompted this re-evaluation, leading to the active development of an ADC that retains the antigen-binding region but employs a direct cytotoxic payload delivery mechanism.
• Furthermore, MacroGenics has also decided against pursuing further internal development of vobra duo (a B7-H3 x CD3 DART molecule, distinct from enoblituzumab but indicative of broader portfolio prioritization concerning B7-H3) and is exploring potential partnering opportunities for that program.[31]
• I-MAB Biopharma (Greater China Rights):
• I-Mab Biopharma had in-licensed the exclusive rights to develop and commercialize enoblituzumab in Greater China from MacroGenics.[11]
• The company initiated a Phase 2 "basket" trial (NCT05338580) in China, evaluating enoblituzumab in combination with pembrolizumab across various solid tumors, including NSCLC and urothelial carcinoma.[11]
• However, in April 2024, I-Mab announced the withdrawal of this Phase 2 trial, citing "company development strategy adjustment".[5] This decision by the regional partner further underscores the challenging development landscape for enoblituzumab as a naked antibody, suggesting that the difficulties or strategic reconsiderations are not confined to MacroGenics' direct development efforts.

Potential Future Directions and Challenges:

The future prospects for enoblituzumab as a standalone naked monoclonal antibody appear uncertain, given the strategic reprioritizations by both MacroGenics and I-Mab. The severe adverse events, particularly the fatal hemorrhagic events observed in the HNSCC trial (NCT04634825), represent a substantial challenge that would need to be thoroughly addressed for any potential revival of this specific molecule in that format.

Despite the setbacks for enoblituzumab itself, the B7-H3 target remains an area of intense interest in oncology. This is evidenced by MacroGenics' continued investment in B7-H3-targeted ADCs like MGC026 [31], and by developments from other companies, such as GSK's B7-H3 ADC (GSK'227, also HS-20093) receiving PRIME (Priority Medicines) designation from the EMA for relapsed extensive-stage small-cell lung cancer.[33]

A critical unknown that would be vital for a complete understanding of enoblituzumab's potential, especially concerning the initial query, is the lack of detailed, published results from the completed pediatric trial NCT02982941. Access to these data would be essential for assessing its safety and efficacy profile in children and young adults with B7-H3-expressing solid tumors.

10. Conclusion and Expert Summary

Enoblituzumab (MGA271) is an Fc-engineered, humanized IgG1κ monoclonal antibody designed to target the B7-H3 immune checkpoint, a protein broadly overexpressed on various tumor types and associated with poor prognosis. Its mechanism of action was intended to be dual: direct tumor cell killing via enhanced ADCC and modulation of T-cell responses by blocking B7-H3's inhibitory functions.

Preclinical studies supported this rationale, demonstrating B7-H3's widespread tumor expression and the anti-tumor activity of enoblituzumab. Early-phase clinical trials, both as monotherapy (NCT01391143) and in the neoadjuvant setting for prostate cancer (NCT02923180), indicated that enoblituzumab was generally well-tolerated and showed preliminary signs of clinical efficacy, including tumor shrinkage and favorable PSA responses. Combination therapy with the PD-1 inhibitor pembrolizumab (NCT02475213) yielded encouraging objective response rates in checkpoint inhibitor-naïve patients with HNSCC and NSCLC (particularly those with PD-L1 <1% expression), although activity was limited in CPI-experienced individuals. Pharmacokinetic studies revealed a generally linear profile with a terminal half-life of approximately 12 days to 3 weeks, depending on the study context and dosing. Pharmacodynamic assessments confirmed target engagement in tumor tissue and demonstrated systemic and local immune modulation, including alterations in T-cell repertoires and cytokine profiles.

However, the clinical development program for enoblituzumab encountered significant challenges. A pivotal Phase 2 trial (NCT04634825) evaluating enoblituzumab in combination with other checkpoint inhibitors for first-line R/M SCCHN was terminated prematurely due to severe safety concerns, specifically fatal hemorrhagic events. This unexpected and serious toxicity marked a critical setback. Furthermore, the dedicated pediatric Phase 1 trial (NCT02982941), which was highlighted in the initial query and is reported as complete, lacks detailed published safety and efficacy results in the available literature, leaving a significant gap in understanding its potential in this vulnerable population.

Reflecting these challenges, both MacroGenics (the originator) and I-MAB Biopharma (holding rights in Greater China) have largely discontinued or withdrawn further clinical development of enoblituzumab in its naked antibody formulation. MacroGenics, for instance, has shifted its B7-H3 targeting strategy towards antibody-drug conjugates (ADCs), such as MGC026, which incorporates the same B7-H3 binding domain as enoblituzumab. This strategic pivot suggests a recognition that while B7-H3 remains a highly attractive therapeutic target in oncology, alternative approaches like ADCs might offer a more favorable therapeutic index or enhanced potency compared to the naked antibody.

The journey of enoblituzumab illustrates the complex and often unpredictable nature of oncology drug development. Initial promise based on a strong mechanistic rationale and early clinical signals can be tempered by later-stage efficacy limitations in broader populations or the emergence of unexpected toxicities. The differential safety and efficacy observed when enoblituzumab was used in various combinations and patient populations also underscore the critical importance of context in designing and interpreting immunotherapy trials.

In summary, while enoblituzumab provided valuable proof-of-concept for targeting B7-H3 and demonstrated some clinical activity, its development as a naked monoclonal antibody has been largely curtailed due to safety concerns and strategic shifts by its developers. The B7-H3 pathway continues to be actively pursued through other therapeutic modalities, leveraging the knowledge gained from programs like enoblituzumab's. For a complete assessment of enoblituzumab, particularly in the pediatric setting, the public dissemination of results from completed trials such as NCT02982941 would be essential.

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