SGN-BB228: An Investigational Bispecific Antibody-Anticalin Fusion for Advanced Solid Tumors

1. Executive Summary

SGN-BB228, also identified as PF-08046049 and formerly PRS-346, is an investigational immuno-oncology agent demonstrating a novel approach to cancer therapy. It is a bispecific antibody-Anticalin fusion protein engineered to dually target CD228 (melanotransferrin) expressed on tumor cells and the 4-1BB (CD137) costimulatory receptor on immune cells. This mechanism is designed to create a conditional activation of 4-1BB signaling, primarily localized within the tumor microenvironment, thereby enhancing T-cell-mediated anti-tumor cytotoxicity while potentially mitigating the systemic toxicities observed with previous 4-1BB agonists.

The development of SGN-BB228 originated from a collaboration between Pieris Pharmaceuticals, which contributed its proprietary Anticalin® technology, and Seagen Inc., which advanced the molecule into clinical trials. Following Pfizer's acquisition of Seagen, SGN-BB228 has become part of Pfizer's extensive oncology pipeline. Currently, SGN-BB228 is undergoing a multi-part Phase 1 clinical trial (NCT05571839) to evaluate its safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity in patients with advanced melanoma and other solid tumors, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, and mesothelioma. Preclinical evidence supports its targeted mechanism and potential efficacy, particularly in models of checkpoint inhibitor resistance. The strategic acquisition by Pfizer underscores the perceived potential of assets like SGN-BB228 and the broader technological platforms they represent. The core promise of SGN-BB228 lies in its potential to offer a more targeted and tolerable approach to 4-1BB agonism, a pathway with significant, yet historically challenging, therapeutic potential in oncology.

2. SGN-BB228: Profile of an Investigational Bispecific Agent

2.1. Nomenclature and Development Codes

The investigational agent SGN-BB228 has been identified by several codes throughout its development, reflecting its journey through different corporate entities and research phases. The primary designation, SGN-BB228, was utilized during its initial clinical trial registrations and by its former sponsor, Seagen Inc..[1] Following Pfizer's acquisition of Seagen, the compound is now also prominently referred to as PF-08046049, particularly within Pfizer's oncology development portfolio and updated clinical trial information.[3] The original code name, PRS-346, was assigned by Pieris Pharmaceuticals, the company that developed the Anticalin® component and initiated the collaboration with Seagen.[4]

Additional synonyms documented for this molecule include anti-CD228/4-1BB bispecific agent SGN-BB228, anti-CD228/anti-4-1BB bispecific agent SGN-BB228, bispecific antibody-anticalin fusion protein SGN-BB228, CD228 x 4-1BB bispecific agent SGN-BB228, and Mabcalin SGN-BB228.[2] This progression of nomenclature—from PRS-346 under Pieris, to SGN-BB228 under Seagen, and subsequently to PF-08046049 under Pfizer—directly mirrors the drug's developmental trajectory and changes in stewardship. This path is characteristic of modern pharmaceutical innovation, often beginning with specialized biotechnology firms like Pieris, advancing through development-focused companies such as Seagen, and potentially culminating with large pharmaceutical organizations like Pfizer, which possess the extensive resources for late-stage clinical development and global commercialization. Comprehending these various identifiers is essential for accurately tracking the compound's research history and associated data across diverse publications and company portfolios.

2.2. Drug Class: Antibody-Anticalin Fusion Bispecific

SGN-BB228 is classified as an "Antibody-Anticalin fusion bispecific" [1], also referred to as a "Mabcalin™ SGN-BB228" [2], or more descriptively, a "costimulatory bispecific molecule composed of a CD228-directed antibody and 4-1BB-directed Anticalin® proteins".[3] Structurally, it comprises a human immunoglobulin G4 (IgG4) monoclonal antibody that targets the cell surface antigen CD228, which is genetically fused to Anticalin proteins engineered to bind the costimulatory receptor 4-1BB.[2]

The selection of an IgG4 backbone for the antibody component targeting CD228 is a noteworthy design choice. IgG4 antibodies are characterized by their inherently lower Fc-mediated effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), compared to other IgG subclasses like IgG1. This reduced effector function is due to weaker binding to Fcγ receptors and C1q. Given that the primary therapeutic mechanism of SGN-BB228 is to crosslink CD228-expressing tumor cells with 4-1BB-expressing T-cells to induce localized 4-1BB signaling and T-cell cytotoxicity [2], potent Fc effector functions from the CD228-binding arm might be counterproductive. Such functions could lead to premature lysis of tumor cells by other immune cells (e.g., NK cells, macrophages) before optimal T-cell engagement, or potentially cause "on-target, off-tumor" toxicities if CD228 has any low-level expression on normal cells that could be targeted by robust Fc functions. By employing an IgG4 backbone, the design strategically emphasizes the bispecific bridging and 4-1BB agonistic activity, rather than direct antibody-mediated killing via the CD228 arm. This approach aligns with the overarching goal of localizing immune activation and potentially enhancing the safety profile of the therapeutic agent. This novel drug class combines the targeting specificity of a monoclonal antibody with the unique binding properties and engineering flexibility of Anticalin proteins, aiming to deliver a differentiated therapeutic strategy.

2.3. The Anticalin® Technology Platform: A Novel Therapeutic Modality

Anticalin® proteins, exclusively commercialized by Pieris Pharmaceuticals (which merged with Palvella Therapeutics in December 2024 [4]), are a class of artificial proteins derived from human lipocalins.[7] Lipocalins are a family of naturally occurring proteins involved in the transport of small molecules. Anticalin proteins are engineered to bind a wide array of antigens, including proteins and small molecules, with high affinity and specificity. They are significantly smaller than conventional antibodies, with a molecular weight of approximately 20 kDa and a structure of about 180 amino acids.[7]

The Anticalin technology platform offers several key advantages that make it attractive for therapeutic development [6]:

• Structure and Binding: Anticalin proteins possess a characteristic barrel structure formed by eight antiparallel β-strands, creating a cup-like binding pocket with four hypervariable loops. This structure can be engineered to bind a diverse range of targets, including those considered too small for traditional antibodies.
• Stability and Monovalency: These proteins exhibit high stability, even at elevated temperatures (up to 70 °C), and their monovalent binding mode prevents unwanted agonist receptor cross-linking, which can be a concern with multivalent binders.
• Bi- and Multispecific Approaches: Anticalin proteins can be genetically fused to other proteins, such as monoclonal antibodies (as in the case of SGN-BB228) or other Anticalin proteins, to create bi- or multispecific drug candidates. This modularity allows for the design of therapeutics that can engage multiple targets or pathways simultaneously.
• Robustness and Delivery: Their small size and inherent stability offer flexibility in formulation and delivery. While SGN-BB228 is administered intravenously, the Anticalin platform itself allows for the development of inhalable proteins for respiratory diseases.
• Safety Profile: Being derived from human lipocalins, Anticalin proteins are anticipated to have a favorable safety profile and have been reported to be well-tolerated in multiple clinical trials to date.
• Manufacturing: Anticalin proteins can be produced in bacterial expression systems, such as E. coli, which can lead to lower production costs and faster development timelines compared to mammalian cell-based antibody production.[6]

In SGN-BB228, the Anticalin component is engineered to target 4-1BB. This utilization of Anticalin technology represents a distinct method for engaging this critical costimulatory receptor, differing from traditional antibody-based 4-1BB agonists and forming an integral part of SGN-BB228's innovative design.

3. Mechanism of Action and Scientific Rationale

3.1. Dual Targeting Strategy: CD228 (Melanotransferrin) and 4-1BB (CD137)

SGN-BB228 employs a dual targeting strategy, a hallmark of its bispecific nature. It is designed to simultaneously engage two distinct molecular targets: CD228, a tumor-associated antigen found on the surface of cancer cells, and 4-1BB, a costimulatory receptor expressed on the surface of immune cells, particularly T-lymphocytes.[1] The antibody component of SGN-BB228 is responsible for binding to CD228 on cancerous cells, while the Anticalin protein component is engineered to bind to 4-1BB on immune cells.[1] This dual interaction is intended to create a physical bridge, bringing tumor-reactive cytotoxic T-cells into close proximity with CD228-expressing tumor cells and providing a potent costimulatory signal to the T-cells.[3] This targeted co-stimulation is the cornerstone of its immunotherapeutic approach, aiming to unleash a focused and powerful anti-tumor immune response.

3.2. CD228 (Melanotransferrin): A Tumor-Associated Antigen

CD228, also known by several synonyms including melanotransferrin, MFI2, MELTF, and p97, is a cell-surface glycoprotein anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) link.[2] It belongs to the transferrin superfamily of iron-binding proteins, although the precise physiological relevance of its iron-binding capability is still under investigation.[2]

A critical characteristic of CD228 for its selection as a therapeutic target is its expression profile. It is reported to have minimal or low expression in most normal adult tissues but is selectively and often highly expressed on the surface of various types of cancer cells.[3] Tumor types noted for CD228 expression include melanoma, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic cancer, and mesothelioma.[3] Beyond serving as a surface marker, CD228 is implicated in several biological processes relevant to cancer progression, such as tumor cell proliferation, angiogenesis, and endothelial cell migration.[9] For instance, overexpression of melanotransferrin in melanoma cells has been shown to contribute to tumor progression by stimulating plasmin generation as well as cell migration and invasion.[9] Consequently, targeting CD228 is viewed as a promising therapeutic strategy in oncology.[10] The tumor-selective expression of CD228 is fundamental to SGN-BB228's mechanism, aiming to direct the therapeutic action and subsequent immune activation specifically to the tumor site, thereby minimizing potential effects on healthy tissues.

The choice of CD228 as the tumor-anchoring target appears strategic not merely for its tumor-restricted expression but also potentially due to its involvement in these pro-tumorigenic biological processes. While the principal function of the CD228-binding arm of SGN-BB228 is to tether the molecule to the tumor and facilitate the crucial 4-1BB interaction with T-cells, the act of antibody binding to CD228 could, in theory, interfere with its native functions that support tumor growth or spread. For example, if CD228 signaling contributes to cell survival or proliferation, antibody engagement might disrupt these pathways. However, it is important to recall that SGN-BB228 utilizes an IgG4 antibody backbone, which is selected for its reduced effector functions. This suggests that direct killing or functional inhibition via the CD228 arm is not the primary design intent. Nonetheless, subtle modulatory effects on CD228's biological activity cannot be entirely discounted and could contribute to the overall therapeutic efficacy, a possibility that warrants further investigation in translational studies.

3.3. 4-1BB (CD137): A Costimulatory Immune Receptor

4-1BB, also known as CD137 and designated as tumor necrosis factor receptor superfamily member 9 (TNFRSF9), is an inducible costimulatory receptor critical for robust immune responses.[2] Unlike constitutively expressed receptors, 4-1BB expression is typically upregulated on various leukocyte subsets following their activation. These include activated CD4+ and CD8+ T-lymphocytes, natural killer (NK) cells, NKT cells, B cells, dendritic cells, and regulatory T cells.[2]

Signaling through the 4-1BB receptor plays a pivotal role in enhancing T-cell functions, including increased proliferation, survival, cytolytic activity, and the production of pro-inflammatory cytokines like interferon-gamma (IFN-γ).[2] These attributes make 4-1BB an attractive target for cancer immunotherapy, as its stimulation can significantly boost the anti-tumor capabilities of T-cells. However, the clinical development of traditional 4-1BB agonist antibodies (which systemically activate 4-1BB) has been fraught with challenges. While showing promise in preclinical models, these systemic agonists have often been associated with limited efficacy at tolerable doses or significant dose-limiting toxicities, most notably hepatotoxicity, at doses required for anti-tumor activity.[8] This narrow therapeutic window has hindered their widespread success. SGN-BB228's design aims to overcome this critical hurdle by delivering 4-1BB stimulation in a more targeted manner.

3.4. Bridging Tumor and Immune Cells for Enhanced Cytotoxicity

The therapeutic strategy of SGN-BB228 hinges on its ability to physically link CD228-expressing tumor cells with 4-1BB-expressing T-cells. Upon administration, SGN-BB228 is designed to simultaneously bind to CD228 on the tumor cell surface via its antibody component and to 4-1BB on T-cells via its Anticalin component.[2] This molecular crosslinking is hypothesized to achieve several critical outcomes. Firstly, it brings cytotoxic T-cells into direct and sustained contact with their tumor targets. Secondly, and crucially, this co-engagement is designed to trigger potent 4-1BB signaling specifically within the tumor microenvironment (TME).[2]

This localized activation of 4-1BB leads to robust co-stimulation of the tumor-reactive T-cells, thereby enhancing their proliferation, survival, and cytotoxic functions, ultimately resulting in the T-cell-mediated lysis of CD228-expressing tumor cells.[2] A key aspect of this design is "conditional activation": the 4-1BB agonistic effect is intended to be primarily dependent on the presence of CD228 on tumor cells. This localized activity is expected to minimize systemic immune activation and thereby reduce the off-target toxicities, such as hepatotoxicity, that have plagued earlier non-targeted 4-1BB agonists.[8] By confining potent immune stimulation to the tumor site, SGN-BB228 aims to expand the therapeutic window for 4-1BB agonism.

Preclinical in vitro studies have provided support for this mechanism, demonstrating that SGN-BB228 induces potent CD228-conditional 4-1BB stimulation and enhances cytotoxic T-cell activation, as referenced by the work of Updegraff et al. in 2022.[8] This conditional activation is the cornerstone of SGN-BB228's proposed advantage, potentially unlocking the full therapeutic efficacy of 4-1BB stimulation by significantly improving its therapeutic index. If this approach proves successful in clinical settings, it could allow for the administration of SGN-BB228 at doses that achieve robust anti-tumor effects without inducing unacceptable systemic side effects, thereby making 4-1BB agonism a more viable and impactful strategy in cancer treatment.

However, the effectiveness of SGN-BB228 will invariably be influenced by the actual expression levels and distribution of CD228 on patient tumors. While CD228 is described as being highly and selectively expressed in the targeted cancer types [3], the inherent heterogeneity of cancer means that inter-tumoral and intra-tumoral variations in CD228 expression are likely. Low or patchy CD228 expression could diminish the efficiency of the "bridge" formation and subsequent T-cell activation, potentially leading to suboptimal therapeutic responses or the emergence of resistant tumor cell populations. The clinical trial protocol (NCT05571839) mandates a pre-treatment biopsy or the submission of archival tissue [16], which could facilitate the assessment of CD228 expression. This information may prove invaluable for developing biomarker strategies for patient selection or stratification in subsequent, later-phase clinical trials, a common and critical step in the development of targeted therapies.

4. Therapeutic Indications and Patient Population

4.1. Targeted Solid Tumors

The ongoing Phase 1 clinical trial, NCT05571839 (also known as SGNBB228-001), is evaluating SGN-BB228 in adult patients with a range of advanced solid malignancies.[1] The study is structured in parts, with specific tumor types eligible for each:

• Parts A (Dose Escalation) and B (Dose and Schedule Optimization): These parts are enrolling patients with metastatic or unresectable cutaneous melanoma.[1]
• Part C (Dose Expansion): This part broadens the scope to include patients with cutaneous melanoma, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic cancer, and mesothelioma.[1]

One source also mentions that SGN-BB228 is under development for "blood cancer" [11], though the current Phase 1 trial's focus is explicitly on solid tumors. This discrepancy might suggest broader, long-term development plans or a minor variation in early-stage reporting. The selection of these particular solid tumors is directly linked to the known or anticipated expression of the target antigen, CD228, on these cancer types. The inclusion of these diverse tumor types in Part C of the Phase 1 trial suggests an element of a "basket trial" design. This strategy allows for efficient preliminary signal-seeking for efficacy across multiple histologies that share the common biological rationale of CD228 expression. Such an approach can accelerate the identification of responsive cancer types, which can then be prioritized for more focused and larger Phase 2 studies, thereby maximizing the potential utility of SGN-BB228 early in its development.

4.2. Rationale for Target Selection based on CD228 Expression

The therapeutic rationale for selecting these specific tumor indications is primarily driven by the expression profile of CD228 (melanotransferrin). As previously detailed, CD228 is reported to be selectively and often highly expressed on cancer cells of these types, including melanoma, NSCLC, CRC, pancreatic cancer, and mesothelioma, while exhibiting minimal expression in normal, healthy tissues.[3] This tumor-restricted expression pattern is fundamental to the intended mechanism of action of SGN-BB228, which aims to localize potent immune activation specifically to the tumor microenvironment, thereby enhancing anti-tumor effects while minimizing potential harm to non-malignant cells.[3] The therapeutic hypothesis posits that by targeting tumors known to express CD228, SGN-BB228 can effectively direct and potentiate T-cell-mediated cytotoxicity against these cancers.

4.3. Patient Population in Clinical Trials

The patient population enrolled in the NCT05571839 study consists of individuals with advanced malignancies who have exhausted or are intolerant to standard therapeutic options, reflecting a high unmet medical need typical for Phase 1 oncology investigations.[8] Key general inclusion criteria for all parts of the study include adults (≥18 years) with histologically or cytologically confirmed metastatic or unresectable solid tumors, whose disease has relapsed, is refractory to, or who are intolerant of standard-of-care therapies. Patients must also have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating relatively good functional status.[8]

Specific criteria apply to certain patient groups. For instance, patients with cutaneous melanoma enrolled in the trial must have received prior treatment with an anti-programmed death-1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) checkpoint inhibitor, administered either alone or in combination with other therapies. Furthermore, melanoma patients with a targetable BRAF mutation must have been treated with, been intolerant of, or been deemed ineligible to receive treatment with a BRAF/MEK targeted therapy prior to study entry.[8] This particular requirement for melanoma patients—having failed prior anti-PD-1/PD-L1 therapy (and BRAF/MEK inhibitors if applicable)—positions SGN-BB228 as a potential therapeutic option for a very challenging, immunotherapy-resistant cohort. Success in this heavily pre-treated population would be highly significant, as it would suggest that SGN-BB228 possesses a mechanism of action capable of overcoming or bypassing common resistance pathways to current checkpoint inhibitors. This aligns with preclinical findings suggesting SGN-BB228 might reinvigorate T-cells unresponsive to PD-1 blockade [20], thus potentially addressing a critical unmet need by engaging a non-redundant anti-tumor immune pathway.

The exclusion of acral, uveal, and mucosal melanoma subtypes from the trial is a significant detail.[14] These rarer melanoma subtypes often exhibit distinct underlying biology and generally have different, often poorer, responses to immunotherapy compared to cutaneous melanoma. This exclusion may stem from several factors: potentially lower or more heterogeneous CD228 expression in these subtypes (though specific data on this is not provided), a strategic decision to initially focus on the more common and relatively homogeneous cutaneous melanoma population for dose-finding and initial efficacy assessment, or known intrinsic resistance mechanisms in these subtypes that SGN-BB228 is not currently anticipated to overcome. This highlights the specific focus of the current investigation within the broader landscape of melanoma.

5. Preclinical Evidence and Foundational Research

5.1. Summary of In Vitro and In Vivo Findings

The rationale for advancing SGN-BB228 into clinical trials is supported by a body of preclinical research, with key findings presented at major scientific conferences. Data on SGN-BB228 (also referred to by its original Pieris code, PRS-346) were showcased at the Society for Immunotherapy of Cancer (SITC) Annual Meeting in 2022.[4] The SITC 2022 presentation characterized SGN-BB228 as a first-in-class CD228-targeted costimulatory antibody-Anticalin bispecific. It was reported to deliver potent and, importantly, CD228-conditional 4-1BB costimulation to tumor-specific T-cells.[20] The conclusions from this presentation suggested therapeutic potential across multiple solid tumor types and provided foundational support for initiating the first-in-human Phase 1 clinical trial.[20]

Further preclinical evidence was presented at the American Association for Cancer Research (AACR) Annual Meeting in 2023.[14] The AACR 2023 data reinforced the earlier findings, showing that SGN-BB228 provides potent and conditional 4-1BB costimulation to T-cells both in vivo and in an in vitro model designed to simulate T-cell exhaustion. A particularly noteworthy observation from this work was that, in the T-cell exhaustion model, SGN-BB228 was able to reinvigorate functionally exhausted T-cells, whereas the anti-PD-1 antibody nivolumab failed to do so, even in the presence of high PD-L1 expression by tumor cells.[20] This finding is particularly compelling as it suggests a mechanistic basis for SGN-BB228's potential utility in patients who have developed resistance to checkpoint inhibitors, a significant clinical challenge. An abstract for the ESMO Congress 2024 (Trial in Progress) also notes that 4-1BB costimulation enhances antitumor T-cell activity through a mechanism distinct from, yet complementary to, the blockade of inhibitory receptors, citing Updegraff 2023 in this context.[14]

5.2. Demonstrated CD228-Conditional 4-1BB Stimulation

A central and consistently emphasized theme in the preclinical evaluation of SGN-BB228 is its ability to induce CD228-conditional 4-1BB stimulation and subsequent cytotoxic T-cell activation.[8] This means that the agonistic activity on the 4-1BB receptor is primarily, if not exclusively, triggered when SGN-BB228 is simultaneously bound to CD228 on the surface of tumor cells. This conditionality is a direct consequence of its bispecific design and is crucial for its proposed therapeutic advantage: localizing potent antitumor immune activity to the tumor microenvironment. Such targeted activation is anticipated to expand the therapeutic window for 4-1BB agonism by minimizing the systemic immune activation that has led to dose-limiting toxicities with earlier, non-conditional 4-1BB agonists.[8] This "CD228-conditional 4-1BB costimulation" is consistently highlighted as the primary differentiating factor and value proposition of SGN-BB228, positioning it not merely as another 4-1BB agonist, but as a precision-guided immunotherapeutic agent.

5.3. Reference to Updegraff et al. 2022

Multiple abstracts related to the SGNBB228-001 clinical trial, including those presented at ASCO 2023 and published by ResearchGate, cite "Updegraff et al 2022" as the source of foundational in vitro data demonstrating SGN-BB228's potent CD228-conditional 4-1BB stimulation and cytotoxic T-cell activation.[8] While the full publication or specific conference presentation details for "Updegraff et al 2022" are not exhaustively provided within the available materials, its findings are consistently invoked as key preclinical evidence supporting the scientific rationale for SGN-BB228's clinical development. It is worth noting that one abstract from ESMO Congress 2024 refers to "Updegraff 2023" [14] in a similar context. This may indicate a follow-up publication, a presentation from a different venue, or a minor variation in citation. However, the core message regarding the preclinical validation of SGN-BB228's conditional mechanism by the Updegraff group remains consistent. For a definitive report outside the constraints of the current information, pinpointing the exact primary reference(s) would be a standard academic practice.

The preclinical finding that SGN-BB228 can reinvigorate exhausted T-cells in vitro, particularly in a setting where anti-PD-1 therapy is ineffective [20], offers a strong mechanistic underpinning for evaluating SGN-BB228 in patient populations that have relapsed after or are refractory to checkpoint inhibitor therapies. T-cell exhaustion is a recognized major mechanism of resistance to immunotherapies like PD-1/PD-L1 blockade. The ability of SGN-BB228 to potentially overcome this exhaustion by providing a potent, direct costimulatory signal via 4-1BB suggests it may engage distinct or complementary cellular pathways. This directly supports the clinical trial's inclusion criteria for melanoma patients who must have received prior anti-PD-(L)-1 therapy [8] and implies that SGN-BB228 could offer a novel therapeutic avenue for patients whose T-cells have become refractory to existing immunotherapies.

6. Clinical Development: The SGNBB228-001 (NCT05571839) Study

6.1. Study Identification and Official Title

The primary clinical investigation for SGN-BB228 is registered on ClinicalTrials.gov under the identifier NCT05571839.[1] The official title of the study is generally "A Phase 1 Study of SGN-BB228 in Advanced Melanoma and Other Solid Tumors," with variations such as "A Study of PF-08046049/SGN-BB228 in Advanced Melanoma and Other Solid Tumors" appearing in some documentation to reflect Pfizer's involvement.[1] The sponsor's study identification code is SGNBB228-001.[8] Other relevant identifiers include IRAS ID 1007351 and Eudract number 2022-502348-11, pertinent to UK and EU regulatory processes, respectively.[1]

6.2. Study Design: Phase 1, Open-Label, Multicenter Trial

The SGNBB228-001 study is a Phase 1, open-label, multicenter clinical trial.[1] It is structured into three main parts to systematically evaluate the investigational agent [1]:

• Part A: Dose Escalation: This initial part is designed to assess the safety and tolerability of SGN-BB228 across different dose levels. The primary goal is to identify dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) or a recommended dose for further study. Approximately 45 participants are planned for this part.
• Part B: Dose and Schedule Optimization (Optional): Based on data from Part A, this part aims to identify the optimal dose and administration schedule for SGN-BB228. This may involve exploring different dosing frequencies (e.g., weekly, biweekly) or cycle lengths (e.g., 28-day vs. 21-day cycles). Approximately 30 subjects are anticipated for this phase.
• Part C: Dose Expansion: In this part, SGN-BB228 will be administered at the dose and schedule determined from Parts A and B to specific cohorts of patients with different tumor types. The objective is to gather further safety data and preliminary evidence of anti-tumor activity in these defined populations. Approximately 200 subjects are planned for enrollment in these expansion cohorts. An ESMO 2024 abstract also mentions that a "biology backfill cohort may enrol with pre-treatment and on-treatment biopsies required" in Part C, underscoring the translational research component.[14]

SGN-BB228 is administered via intravenous (IV) infusion.[1] In Part A, participants typically receive the study drug twice within a 28-day cycle. Part B may explore this 28-day cycle or an alternative 21-day cycle. Participants in Part C will be treated according to the schedule deemed optimal from the preceding parts.[1] Patient assessments include tumor imaging scans conducted approximately every 6 weeks to monitor for changes in the cancer.[1] This multi-part design is an adaptive strategy common in early oncology development, allowing for flexibility in dose-finding, schedule refinement, and initial efficacy signal-seeking across various tumor types within a single, efficient protocol.

6.3. Primary Objectives

The primary objectives of the SGNBB228-001 study are centered on evaluating the safety and tolerability profile of SGN-BB228.[1] Specific primary endpoints include:

• The rate and severity of adverse events (AEs).[8]
• The incidence and nature of laboratory abnormalities.[8]
• The number of participants experiencing dose-limiting toxicities (DLTs), particularly during the dose escalation phase (Part A).[8]
• Assessment of cumulative dose-level safety.[8]
• Identification of a recommended dose and schedule for subsequent investigation (often referred to as the Recommended Phase 2 Dose, RP2D).[1]

6.4. Secondary Objectives

Secondary objectives aim to provide further insights into the drug's characteristics and potential clinical activity [4]:

• Characterization of the pharmacokinetics (PK) of SGN-BB228, including parameters such as Area Under the Curve (AUC), maximum concentration (Cmax), terminal half-life (t1/2), and trough concentration (Ctrough).[8]
• Preliminary assessment of anti-tumor activity, measured by:
• Objective Response Rate (ORR), defined as the proportion of participants achieving a complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).
• Duration of Response (DOR).
• Progression-Free Survival (PFS).
• Overall Survival (OS).
• Evaluation of the incidence of anti-drug antibodies (ADAs) to SGN-BB228.

6.5. Key Eligibility Criteria (Inclusion and Exclusion)

The study enrolls adult patients (≥18 years of age) with histologically or cytologically confirmed metastatic or unresectable malignancies who meet specific criteria.[8]

Key Inclusion Criteria:

• Disease that is relapsed, refractory, or for which the patient is intolerant to standard-of-care therapies.
• Specific tumor types are required for enrollment into Parts A, B, and C, as detailed in Section 4.1 (e.g., cutaneous melanoma for Parts A/B; cutaneous melanoma, NSCLC, CRC, pancreatic cancer, mesothelioma for Part C).
• ECOG Performance Status of 0 or 1.
• Presence of measurable disease per RECIST v1.1 at baseline.
• Adequate organ function (hematologic, renal, hepatic).
• Submission of a pre-treatment tumor biopsy or archival tumor tissue is mandatory.
• For patients with cutaneous melanoma: documented prior treatment with an anti-PD-1 or anti-PD-L1 agent. If the tumor harbors a targetable BRAF mutation, patients must have received prior BRAF/MEK targeted therapy, been intolerant to it, or been deemed ineligible for such treatment.

Key Exclusion Criteria:

• Prior therapy with any agent targeting CD228 or 4-1BB.
• Active central nervous system (CNS) metastases or leptomeningeal disease. (However, patients with previously treated and stable brain metastases may be eligible if they meet specific criteria, including being off corticosteroids for at least 7 days prior to the first dose of SGN-BB228).
• History of another malignancy within 3 years before the first dose of the study drug, with exceptions for malignancies with a negligible risk of metastasis or death.
• Receipt of certain immunotherapy, biologics, or other approved or investigational antitumor treatments within specified washout periods prior to the first dose of SGN-BB228.
• Specific melanoma subtypes, including acral, uveal, and mucosal melanoma, are excluded.

6.6. Current Recruitment Status, Timelines, and Participating Regions

The SGNBB228-001 trial was initially sponsored by Seagen Inc..[1] Following its acquisition, Pfizer is now the legal entity responsible for the study.[14] The recruitment status has been listed as "Recruiting" in several sources [18], though some site-specific or older entries indicate "Active Not-enrolling" [16], which can reflect the dynamic nature of trial enrollment across multiple sites or phases.

The study commenced in January 2023, with the first patient dosed that month.[4] The estimated primary completion date and study completion date have seen adjustments, a common occurrence in clinical trial management. For instance, the estimated primary completion date has shifted from October 2025 to November 2026, and more recently to April 2027. Similarly, the estimated study completion date has moved from an earlier projection to November 2027, and then to April 2028.[16] These evolving timelines can be attributed to various factors inherent in clinical research, such as recruitment rates, protocol amendments based on emerging data, safety observations, or strategic decisions by the sponsor. This variability underscores that clinical trial timelines are dynamic projections.

The target enrollment for the trial is approximately 275 participants globally, distributed across Part A (~45), Part B (~30), and Part C (~200).[1] The trial is being conducted in multiple countries, including the United States, Canada, France, Germany, Switzerland, and the United Kingdom.[14] Specific academic centers such as UCLA and NYU Langone Health are listed as participating sites.[17] In the UK, the London - London Bridge Research Ethics Committee provided a Further Information Favourable Opinion on July 26, 2023.[1] The multinational nature of the trial, evidenced by the Eudract number and European sites, suggests a global development strategy aimed at eventual registration in major markets.

Table 1: Summary of NCT05571839 Clinical Trial Parameters

Parameter	Details
Identifier	NCT05571839 1
Official Title	A Phase 1 Study of SGN-BB228 in Advanced Melanoma and Other Solid Tumors (variations exist including PF-08046049) 1
Phase	Phase 1 1
Study Design	Open-label, multicenter, 3-part (A: Dose Escalation; B: Dose/Schedule Optimization; C: Dose Expansion) 1
Sponsor(s)	Seagen Inc. (now Pfizer) 1
Primary Objectives	Evaluate safety and tolerability; determine DLTs; identify MTD/RP2D 1
Key Secondary Objectives	PK, ORR, DOR, PFS, OS, incidence of ADAs 4
Target Enrollment	Approx. 275 participants (Part A: ~45; Part B: ~30; Part C: ~200) 1
Key Inclusion (Brief)	Adults ≥18 yrs; advanced/metastatic solid tumors (melanoma for A/B; melanoma, NSCLC, CRC, pancreatic ca., mesothelioma for C); relapsed/refractory to SOC; ECOG 0-1 8
Key Exclusion (Brief)	Prior CD228/4-1BB therapy; active CNS metastases (unless stable/treated); certain melanoma subtypes (acral, uveal, mucosal) 14
Intervention	SGN-BB228 (PF-08046049); IV infusion; various schedules explored (e.g., twice per 28-day cycle) 1
Current Status	Recruiting (some sources may indicate "Active, Not Enrolling" for specific sites/parts) 16
Start Date	January 2023 4
Est. Primary Completion	April 2027 (subject to change) 20
Est. Study Completion	April 2028 (subject to change) 20
Locations	USA, Canada, France, Germany, Switzerland, United Kingdom 14

7. Development and Corporate Landscape

7.1. Origin and Initial Collaboration: Pieris Pharmaceuticals and Seagen Inc.

The development of SGN-BB228, originally designated PRS-346 by Pieris Pharmaceuticals, stemmed from an immuno-oncology research and development collaboration established between Pieris and Seagen Inc..[4] Under this partnership, Pieris contributed its proprietary Anticalin® technology platform. Specifically, PRS-346 comprised an Anticalin-based component targeting the 4-1BB receptor, which was then fused to an antibody developed by Seagen that targets the CD228 antigen on tumor cells.[2] This collaboration was structured to leverage Pieris's expertise in Anticalin protein engineering and Seagen's capabilities in antibody development and oncology clinical progression.

As part of the agreement, Pieris Pharmaceuticals was eligible for milestone payments. Notably, Pieris announced the achievement of a $5 million milestone payment from Seagen following the dosing of the first patient in the Seagen-sponsored Phase 1 study of SGN-BB228 (NCT05571839) in January 2023.[4] The collaboration between the two companies encompassed up to three distinct immuno-oncology programs, with Pieris retaining an opt-in option for U.S. co-promotion for one of these programs.[4] This arrangement is illustrative of a common model in the biotechnology industry, where innovative platform technology companies like Pieris partner with more development-focused entities like Seagen to advance novel therapeutic candidates through preclinical and clinical stages.

7.2. Impact of Pfizer's Acquisition of Seagen on SGN-BB228 Development

A significant corporate development impacting SGN-BB228 was Pfizer's acquisition of Seagen Inc. Pfizer announced its intent to acquire Seagen on March 13, 2023, and the transaction, valued at approximately $43 billion, was successfully completed on December 14, 2023.[25] Pfizer's strategic rationale for this major acquisition centered on Seagen's world-leading expertise in Antibody-Drug Conjugate (ADC) technology and its robust pipeline of transformative cancer medicines.[25]

The integration of Seagen into Pfizer has substantially expanded Pfizer's oncology portfolio, reportedly doubling its pipeline to 60 programs. These programs span multiple therapeutic modalities, including ADCs, small molecules, other immunotherapies, and bispecific antibodies such as SGN-BB228.[25] SGN-BB228, now also identified by the Pfizer development code PF-08046049, is listed within Pfizer's oncology development pipeline.[3] Pfizer has stated its intention to leverage its extensive capabilities in protein engineering and medicinal chemistry to advance Seagen's technologies, which would include assets like SGN-BB228.[25] Reflecting this transition, the ESMO Congress 2024 abstract for the SGNBB228-001 trial identifies Pfizer as the "legal entity responsible for the study" and explicitly notes Seagen's acquisition by Pfizer.[14]

The acquisition by a global pharmaceutical leader like Pfizer, with its vast resources in research and development, manufacturing, and commercialization, could significantly influence the future trajectory of SGN-BB228. This new stewardship could potentially accelerate and broaden its clinical development program. However, SGN-BB228 now resides within a much larger and more diverse oncology portfolio. While it may benefit from greater resources if prioritized, it will also face internal competition for funding and focus from other promising assets within Pfizer's expanded pipeline. Its continued advancement will depend on emerging clinical data, its perceived strategic fit, and ongoing portfolio evaluations by Pfizer.

The Anticalin technology from Pieris Pharmaceuticals remains a foundational component of SGN-BB228. The milestone payment to Pieris upon Phase 1 initiation validated the clinical progression of this technology. Pieris Pharmaceuticals itself underwent a corporate change, merging with Palvella Therapeutics in December 2024.[4] Palvella's primary focus is on developing therapies for serious, rare genetic skin diseases.[6] While existing contractual obligations related to SGN-BB228 are expected to be honored by the merged entity, the new company's strategic R&D priorities may differ from those of the standalone Pieris, which had a broader focus that included oncology. This could influence future collaborations or the active pursuit of new Anticalin-based oncology programs beyond current commitments.

Table 2: Timeline of Key Development and Corporate Milestones for SGN-BB228

Date/Period	Event	Key Entities Involved	Significance
Prior to 2022	Pieris-Seagen collaboration established for immuno-oncology programs including PRS-346 (SGN-BB228)	Pieris, Seagen	Foundation of SGN-BB228 development, combining Anticalin technology with antibody expertise 4
Nov 2022	IND accepted for SGN-BB228 (PRS-346) Phase 1 study; Preclinical data presentation at SITC 2022	Seagen, Pieris	Regulatory clearance for clinical trial initiation; Public disclosure of preclinical rationale 5
Jan 2023	First patient dosed in SGNBB228-001 (NCT05571839) Phase 1 trial	Seagen	Clinical trial commencement; Pieris receives $5M milestone payment 4
Mar 13, 2023	Pfizer announces intention to acquire Seagen	Pfizer, Seagen	Major corporate development with potential to impact SGN-BB228's future 26
Apr 2023	Preclinical data for SGN-BB228 presented at AACR 2023	Seagen/Pfizer, Pieris (dev)	Further dissemination of preclinical findings, including activity in T-cell exhaustion models 20
Jun 2023	SGNBB228-001 (NCT05571839) Trial-in-Progress abstract published (ASCO 2023)	Seagen	Public update on clinical trial design and status 8
Jul 26, 2023	UK REC provides Favourable Opinion for SGNBB228-001 trial	Seagen, UK REC	Regulatory green light for trial conduct in the UK 1
Dec 14, 2023	Pfizer completes acquisition of Seagen	Pfizer, Seagen	SGN-BB228 becomes a Pfizer asset (PF-08046049); Seagen integrated into Pfizer Oncology 25
Dec 2024	Pieris Pharmaceuticals merges with Palvella Therapeutics	Pieris, Palvella	Corporate change for the Anticalin technology originator; potential shift in strategic focus for the new entity 4
Anticipated 2024	ESMO Congress 2024 Trial-in-Progress abstract for SGN-BB228 (PF-08046049)	Pfizer	Continued updates on the Phase 1 study under Pfizer's stewardship 14

8. Regulatory Overview

8.1. Current Investigational Status

SGN-BB228, also known as PF-08046049, is currently an investigational compound. Its safety and efficacy have not yet been established by regulatory authorities such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[3] The molecule is in the early stages of clinical development, specifically undergoing a Phase 1 clinical trial (NCT05571839) to assess these parameters in human subjects, as detailed previously.

8.2. Regulatory Designations (FDA/EMA)

Based on the available information, SGN-BB228 (or its alternative identifiers PF-08046049, PRS-346) has not yet received any specific regulatory designations from the FDA or EMA. Such designations include Orphan Drug Designation, Fast Track, Breakthrough Therapy, or Priority Review in the U.S., or PRIME (Priority Medicines) scheme in the E.U. Searches of publicly accessible FDA orphan drug databases and EMA orphan medicinal product resources did not yield specific orphan designations for SGN-BB228 for the indications currently under investigation in the NCT05571839 trial.[29]

The absence of such designations at this early Phase 1 stage of development is not uncommon. Regulatory designations like Orphan Drug status (granted for diseases affecting limited patient populations [31]) or those designed to expedite development and review (like Breakthrough Therapy or Fast Track) are typically pursued when sufficient preclinical and, more importantly, compelling early clinical data suggest significant therapeutic potential, a substantial improvement over available therapies, or relevance to a qualifying rare disease. As more clinical data emerge from the ongoing Phase 1 trial, particularly from the dose expansion cohorts (Part C) focusing on specific tumor types, the sponsor (Pfizer) may have the opportunity to seek these designations. Strong, early efficacy signals in an indication with high unmet medical need or in a rare cancer type (e.g., mesothelioma or specific subtypes of pancreatic cancer that might meet orphan criteria) would be key triggers for such applications. Obtaining these designations can offer various benefits, including protocol assistance, market exclusivity, and accelerated review pathways, which can significantly impact the drug's development timeline and commercial prospects.

9. Expert Analysis and Future Perspectives

9.1. Synthesis of SGN-BB228's Potential

SGN-BB228 represents a sophisticated approach in immuno-oncology, characterized by its novel bispecific antibody-Anticalin fusion structure and its dual-targeting mechanism. By engaging CD228 on tumor cells and simultaneously delivering a costimulatory signal through 4-1BB on T-cells, SGN-BB228 aims to achieve CD228-conditional 4-1BB activation. This strategy is designed to concentrate potent immune stimulation within the tumor microenvironment, potentially overcoming the systemic toxicity issues that have historically limited the therapeutic application of systemic 4-1BB agonists. The selection of CD228, an antigen with reported tumor-selective expression across various solid malignancies, is key to this targeted approach. Furthermore, its development in patient populations that are often refractory to existing treatments, including checkpoint inhibitors, highlights its potential to address significant unmet medical needs. The Anticalin platform, contributed by Pieris Pharmaceuticals, plays a crucial role in enabling this precision-guided immunomodulation, offering unique engineering flexibility for the 4-1BB binding moiety. If successful, SGN-BB228 could validate a safer and more effective way to harness the powerful anti-tumor effects of 4-1BB co-stimulation.

9.2. Potential Advantages and Challenges of the Bispecific Anticalin Approach

The bispecific antibody-Anticalin fusion design of SGN-BB228 offers several potential advantages:

• Improved Therapeutic Index for 4-1BB Agonism: The primary anticipated benefit is an enhanced safety profile compared to traditional systemic 4-1BB agonists, achieved through tumor-localized, conditional activation of 4-1BB. This could allow for more effective dosing and broader clinical utility.
• Overcoming Checkpoint Inhibitor Resistance: Preclinical data suggest SGN-BB228 may activate T-cells in a manner distinct from PD-1/PD-L1 blockade and could potentially reinvigorate exhausted T-cells [20], offering a new therapeutic option for patients who have failed current immunotherapies.
• Engineering Flexibility of Anticalins: The Anticalin platform provides advantages in terms of protein engineering, stability, and potentially favorable manufacturing characteristics.[6]
• Targeted Antigen Selection: CD228 is reported to be a tumor-associated antigen with relatively selective expression, which is crucial for the targeted delivery of the 4-1BB agonistic effect.

However, the development of SGN-BB228 also faces several challenges:

• Dependence on CD228 Expression: The efficacy of SGN-BB228 is critically dependent on sufficient and relatively homogeneous expression of CD228 on the target tumor cells. Intra- and inter-tumoral heterogeneity in CD228 expression could limit responses.
• Potential On-Target, Off-Tumor Toxicities: Despite reports of minimal CD228 expression in normal tissues, if significant expression is discovered on critical healthy cells, on-target (CD228-mediated), off-tumor toxicities could still arise.
• Manufacturing and Stability Complexity: While Anticalins themselves are robust, the manufacturing and long-term stability of complex bispecific fusion proteins can sometimes present challenges.
• Immunogenicity: As with any biologic therapeutic, particularly one containing novel protein scaffolds like Anticalins, there is a potential for immunogenicity. The development of anti-drug antibodies (ADAs) could impact efficacy or safety, and this is being monitored as a secondary endpoint in the clinical trial.[8]
• Competitive Landscape: The field of immuno-oncology is highly competitive, with numerous advanced therapeutic modalities under development. SGN-BB228 will need to demonstrate a clear clinical benefit to establish its place.

9.3. Outlook for Ongoing and Future Clinical Development

The immediate future of SGN-BB228 hinges on the successful completion and outcomes of the ongoing Phase 1 SGNBB228-001 (NCT05571839) study. Establishing a safe and tolerable dose (RP2D) and demonstrating preliminary signals of anti-tumor efficacy in the dose expansion cohorts (Part C) are paramount. Positive data from these specific tumor cohorts will guide decisions for subsequent Phase 2 development, likely focusing on those cancer types where the most promising activity is observed.

The ESMO 2024 Trial-in-Progress abstract for SGN-BB228 mentions the "potential for future combination dosing".[14] Given its immune-activating mechanism, exploring SGN-BB228 in combination with other anti-cancer agents is a logical next step. Potential combination partners could include other checkpoint inhibitors (to potentially achieve synergistic effects beyond overcoming resistance), chemotherapy or radiotherapy (to enhance antigen presentation and T-cell priming), or other targeted therapies relevant to the specific tumor biology of responsive indications.

A critical aspect of future development will be robust biomarker identification and validation. While the current trial requires pre-treatment biopsies [16], further translational research, supported by initiatives like the "biology backfill cohort" [14], will be essential to understand the correlation between CD228 expression levels (and its heterogeneity), 4-1BB expression on immune cells, baseline tumor immune infiltrate, and clinical outcomes. This will be crucial for developing patient selection strategies for later-phase trials to enrich for responsive populations.

Ultimately, the long-term development trajectory of SGN-BB228 will be heavily influenced by the strategic decisions of Pfizer, based on the emerging clinical data, the competitive landscape, and the overall priorities within its extensive oncology portfolio. The success of SGN-BB228 could also serve as a significant validation for the broader "Mabcalin" (antibody-Anticalin fusion) platform. If SGN-BB228 demonstrates a markedly improved therapeutic index for 4-1BB agonism due to its CD228-conditional, Anticalin-mediated activation, it would provide strong clinical proof-of-concept for this engineering approach. This could de-risk and encourage the development of other Anticalin-based bispecifics designed for conditional immunomodulation or targeted delivery, leveraging the unique attributes of the Anticalin scaffold. While SGN-BB228 itself is an intravenously administered antibody fusion, the inherent properties of Anticalins, such as their small size and stability [6], might open avenues for alternative formulations or delivery routes for future Anticalin-based therapeutics, which is a more speculative but relevant consideration for the underlying technology.

10. Conclusion and Strategic Recommendations

10.1. Recap of SGN-BB228's Key Attributes and Development Progress

SGN-BB228 (PF-08046049) is a novel, investigational bispecific antibody-Anticalin fusion protein engineered for conditional activation of the 4-1BB costimulatory pathway on T-cells. Its unique design involves targeting CD228 (melanotransferrin) on tumor cells and 4-1BB (CD137) on T-lymphocytes, aiming to create a molecular bridge that localizes potent immune stimulation within the tumor microenvironment. This approach seeks to overcome the systemic toxicities that have hampered the development of previous, non-targeted 4-1BB agonists, thereby potentially widening the therapeutic window.

The compound originated from a collaboration between Pieris Pharmaceuticals (Anticalin technology) and Seagen Inc., and is now part of Pfizer's oncology pipeline following Pfizer's acquisition of Seagen. SGN-BB228 is currently in a multi-part Phase 1 clinical trial (NCT05571839) evaluating its safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity in patients with advanced melanoma and other selected solid tumors known for CD228 expression, many of whom have exhausted standard treatment options. Preclinical studies have supported its mechanism of action, demonstrating CD228-dependent 4-1BB stimulation and T-cell activation, including in models of checkpoint inhibitor resistance.

10.2. Recommendations for Future Research Focus or Development Strategies

Based on the available information and the nature of SGN-BB228, several strategic considerations and recommendations for its future development can be proposed:

• Prioritize Translational Research and Biomarker Development: A crucial strategic imperative is the robust development of validated biomarker assays, particularly for CD228 expression. This should include quantitative assessment and evaluation of expression heterogeneity. Understanding the correlation between CD228 levels, the tumor immune microenvironment (e.g., baseline T-cell infiltration, 4-1BB expression on T-cells), and clinical response will be vital for optimizing patient selection in future trials. The planned "biology backfill cohort" in the Phase 1 study [14] should be fully leveraged to identify predictive biomarkers that can guide patient stratification, potentially leading to improved efficacy outcomes and a more streamlined regulatory path. Consideration of a companion diagnostic should be an early strategic discussion.
• Focus on Demonstrating a Differentiated Safety Profile: Given the historical challenges with systemic 4-1BB agonism, a key focus must be on meticulously collecting and clearly presenting safety data that demonstrates a favorable and manageable tolerability profile for SGN-BB228. Particular attention should be paid to potential liver toxicity and other systemic immune-related adverse events. Successfully differentiating SGN-BB228 on safety grounds compared to historical non-conditional 4-1BB agonists will be critical for its clinical acceptance and commercial viability.
• Rationally Design Combination Strategies: Upon establishment of the monotherapy safety profile and recommended Phase 2 dose, and guided by emerging efficacy signals and translational data, the development of combination strategies should be pursued. Potential partners could include:
• Other immunotherapies, if synergistic mechanisms are identified beyond simply overcoming resistance to prior checkpoint blockade.
• Standard-of-care chemotherapy or radiotherapy, which can induce immunogenic cell death and enhance antigen presentation, potentially priming the tumor microenvironment for SGN-BB228 activity.
• Other targeted agents, depending on the specific tumor types showing promise and their underlying molecular drivers.
• Strategic Cohort Expansion and Indication Prioritization: Data from the Phase 1 Part C expansion cohorts will be critical. Indications showing the most robust and durable responses should be prioritized for dedicated Phase 2 studies. Consideration could also be given to exploring other CD228-positive tumor types not currently included in the Phase 1 expansion, if a strong biological and clinical rationale emerges (e.g., the "blood cancer" reference [11], contingent on confirmed CD228 expression and relevance).
• Long-Term Follow-Up and Resistance Mechanisms: Ensure robust long-term follow-up of treated patients to assess the durability of responses and monitor for any late-onset toxicities. Translational studies should also investigate mechanisms of acquired resistance to SGN-BB228, should they emerge, to inform future therapeutic strategies or next-generation drug design.
• Comparative Assessment (Future): As SGN-BB228 progresses, if early trials yield positive results, future development plans will need to consider its positioning relative to other emerging immunotherapies and targeted agents, potentially through comparative effectiveness studies in later phases.

The development of SGN-BB228 is a promising endeavor in the quest for more effective and safer cancer immunotherapies. Its unique mechanism offers a potential solution to a long-standing challenge in harnessing the power of 4-1BB co-stimulation. Rigorous clinical evaluation, coupled with insightful translational research and strategic development planning under Pfizer's stewardship, will determine its ultimate role in the oncology treatment paradigm.

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