ZB-004 (XmAb10717): A Bioengineered CTLA-4-Ig Fusion Protein for Autoimmune Diseases

1. Introduction to ZB-004 (XmAb10717)

1.1. Overview and Therapeutic Class

ZB-004, also identified by the research designation XmAb10717, is an investigational biopharmaceutical agent currently under clinical development.[1] It is a bioengineered fusion protein, specifically classified as a cytotoxic T-lymphocyte-associated antigen 4‑immunoglobulin (CTLA-4-Ig).[3] Functionally, ZB-004 acts as an immunomodulator by selectively inhibiting the costimulatory signals essential for T-lymphocyte activation, a pivotal process in the adaptive immune response.[2] The primary therapeutic focus for ZB-004 is the treatment of autoimmune diseases, conditions wherein aberrant T-cell activity contributes significantly to pathogenesis.[1]

ZB-004 represents a second-generation therapeutic within the CTLA-4-Ig class. This classification is underscored by its design, which incorporates specific bioengineering modifications aimed at optimizing its pharmacological profile relative to earlier CTLA-4-Ig molecules, such as abatacept. The explicit design goals for ZB-004 include "increased binding affinity" to its target ligands (CD80 and CD86) and an "extended half-life".[3] These enhancements are intended to build upon the clinically validated mechanism of action of CTLA-4-Ig [7] by potentially offering superior pharmacological properties. Such improvements could manifest as enhanced efficacy, possibly due to more potent target engagement, and improved patient convenience through a less frequent dosing schedule.

1.2. Originator and Current Developer

The conception and initial development of ZB-004 (XmAb10717) were undertaken by Xencor, Inc. This development leveraged Xencor's proprietary XmAb® antibody engineering platform, with a key component being the Xtend™ Fc technology, specifically designed to prolong the circulating half-life of therapeutic proteins.[2]

In November 2020, Xencor, Inc. executed a licensing agreement that granted exclusive worldwide rights for the continued development and subsequent commercialization of XmAb10717 (ZB-004), along with two other preclinical assets (XmAb6755 and XPro9523), to a newly formed, privately held biotechnology company.[9] The entities currently spearheading the clinical advancement of ZB-004 are Zenas BioPharma LLC and its affiliated company, Shanghai Zenas Biotechnology Co., Ltd..[2] This transition in stewardship occurred while ZB-004 was in the preclinical phase of development, with Zenas BioPharma subsequently guiding the molecule into Phase 1 clinical evaluation.[2]

The transfer of ZB-004's development from Xencor to Zenas BioPharma illustrates a common strategic approach within the biopharmaceutical sector. Xencor, as a company with a strong focus on technology platforms and early-stage drug discovery, excels in innovating and de-risking novel therapeutic candidates through advanced protein engineering. Their business model frequently involves out-licensing or partnering programs after initial validation.[9] Conversely, Zenas BioPharma was established with a specific mission to undertake later-stage clinical development and global commercialization of immune-based therapies. The acquisition of assets like ZB-004 aligns with Zenas' strategy to construct a robust pipeline by securing promising, engineered molecules that possess a strong scientific rationale and the potential for significant clinical differentiation.[2] This division of labor allows each organization to capitalize on its core competencies, potentially streamlining and accelerating the overall development trajectory of ZB-004.

Table 1: ZB-004 (XmAb10717) - Key Characteristics

Feature	Description	References
Synonyms	ZB004, ZB 004, XmAb10717	2
Drug Class	CTLA-4-Ig Fusion Protein, Immunomodulator	2
Originator	Xencor, Inc.	2
Current Developer	Zenas BioPharma LLC / Shanghai Zenas Biotechnology Co., Ltd.	2
Molecular Target	CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells	3
Key Engineering Features	CTLA-4 Extracellular Domain (ECD) substitutions for increased CD80/CD86 binding affinity	3
	Xtend™ Fc Domain (hybrid IgG1/2 Fc region with M428L and N434S substitutions) for extended plasma half-life	3

2. Molecular Design and Mechanism of Action

2.1. CTLA-4-Ig Fusion Protein Construct

ZB-004 is a sophisticated, bioengineered recombinant fusion protein. Its fundamental architecture involves the genetic fusion of the extracellular domain (ECD) of human Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) with a modified human immunoglobulin (Ig) Fc domain.[3] CTLA-4 is a critical natural negative regulator of T-cell immune responses. By presenting the ligand-binding portion of CTLA-4 in a soluble, stable, and pharmacokinetically optimized format, ZB-004 is designed to mimic and amplify this natural inhibitory function.[3] The therapeutic principle of CTLA-4-Ig fusion proteins is well-established in the treatment of autoimmune diseases, with existing drugs like abatacept and belatacept serving as precedents.[7]

2.2. Bioengineering for Enhanced Affinity: CTLA-4 ECD Modifications

A key element of ZB-004's design involves specific modifications within its CTLA-4 ECD component. The molecule incorporates two amino acid substitutions in this domain, although the precise identities of these substituted residues are not disclosed in the available abstracts.[3] The explicit purpose of these engineered changes to the CTLA-4 ECD is to augment the binding affinity of ZB-004 for its molecular targets: CD80 (also known as B7-1) and CD86 (also known as B7-2). These targets are crucial costimulatory molecules expressed on the surface of antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B-cells.[3] Xencor's patent US9884902B2 details various mutations within the CTLA-4 ECD that can significantly enhance binding affinity to CD80 and CD86, providing a likely technological foundation for the specific modifications incorporated into ZB-004.[12]

The engineering of the CTLA-4 ECD for heightened affinity to CD80/CD86 represents a rational approach to potentially increase the therapeutic potency of ZB-004. An enhanced binding affinity could facilitate more effective blockade of the CD28-CD80/CD86 costimulatory axis, possibly at lower drug concentrations or achieving more complete and sustained target saturation, particularly in inflammatory microenvironments where ligand density might be high. The strength of the interaction between a therapeutic protein and its target is a direct determinant of its biological activity. Consequently, a higher affinity for CD80 and CD86 enables ZB-004 to more effectively outcompete the endogenous CD28 receptor for binding to these ligands.[3] This improved competitive binding could translate to a lower administered dose required to achieve the desired level of T-cell costimulation blockade, which in turn might improve the therapeutic index by minimizing potential off-target effects or dose-related toxicities.

2.3. Bioengineering for Extended Half-Life: The Xtend™ Fc Domain and FcRn Interaction

The Fc domain of ZB-004 is a hybrid construct, incorporating elements from human IgG1 and IgG2 constant regions.[3] This hybrid design may be selected to optimize the balance between effector functions (or lack thereof, if ablated) and pharmacokinetic properties. A critical feature of this Fc domain is the inclusion of two specific amino acid substitutions: M428L (methionine at position 428 mutated to leucine) and N434S (asparagine at position 434 mutated to serine), according to EU numbering conventions. This modified Fc region is a component of Xencor's proprietary Xtend™ Fc technology platform.[3]

The Xtend™ Fc domain, by virtue of these M428L/N434S substitutions, is specifically engineered to exhibit increased binding affinity for the neonatal Fc receptor (FcRn).[3] FcRn is a pivotal receptor in maintaining IgG homeostasis. It binds to the Fc region of IgG within the acidic environment of endosomes following cellular pinocytosis. This binding rescues the IgG from lysosomal degradation and facilitates its recycling back to the cell surface, where it is released into the neutral pH of the bloodstream. An enhanced affinity for FcRn leads to more efficient recycling and a significantly reduced rate of catabolism, thereby prolonging the protein's persistence in circulation. Xencor's patent literature, such as US9884902B2 and US10793632B2, describes various Fc variants, including those with altered FcRn binding characteristics, designed to extend in vivo half-life.[12] The primary objective of incorporating this Fc engineering into ZB-004 is to achieve a marked extension of its in vivo circulating half-life, which would consequently allow for a reduced frequency of administration to patients.[3]

The successful application of Xtend™ Fc technology to ZB-004, as evidenced by the observed 8-18 day half-life in the Phase 1 study [3], represents a significant potential clinical and pharmacoeconomic advantage, particularly in the context of managing chronic autoimmune diseases. Conditions of this nature often necessitate long-term, if not lifelong, therapeutic intervention. A drug candidate with an extended half-life that permits substantially less frequent dosing regimens—for instance, subcutaneous injections administered every few weeks or even monthly, as opposed to more frequent schedules like weekly or bi-weekly—can dramatically improve patient convenience, reduce treatment burden, and foster better adherence to therapy. Enhanced adherence is a critical determinant of long-term treatment success. Moreover, from a healthcare system and patient perspective, a reduced dosing frequency can translate to lower annualized treatment costs, encompassing fewer drug administrations and potentially less frequent clinical monitoring. This attribute is a key differentiator for novel biologic agents entering competitive therapeutic landscapes.

2.4. Target Engagement and Mechanism of T-Cell Costimulation Blockade

ZB-004 exerts its immunomodulatory effects by specifically binding to the CD80 and CD86 molecules, which are expressed on the surface of APCs.[3] This binding action physically obstructs the interaction between CD80/CD86 on APCs and their cognate receptor, CD28, which is constitutively expressed on T-lymphocytes.[3]

The interaction between CD28 on T-cells and CD80/CD86 on APCs provides a critical "second signal," or costimulatory signal. This signal, in conjunction with the "first signal" delivered through the T-cell receptor (TCR) upon engagement with peptide-MHC (Major Histocompatibility Complex) complexes on APCs, is indispensable for the full activation, proliferation, cytokine production, and differentiation of T-cells into effector cells. By competitively inhibiting this vital CD28-mediated costimulatory pathway, ZB-004 effectively dampens T-cell-driven immune responses. This modulation is achieved without inducing broad immunosuppression or lymphocyte depletion, offering a more targeted approach. Such targeted immunomodulation is particularly relevant in the context of autoimmune diseases, where the dysregulation of autoreactive T-cells is a central driver of tissue damage and disease pathology.[7]

The mechanism of ZB-004, by focusing on the blockade of CD28-mediated costimulation, aims for a more refined immunomodulation compared to therapeutic strategies that involve widespread lymphocyte depletion or global inhibition of cytokine pathways. This specificity inherent in targeting "Signal 2" of T-cell activation may offer a more favorable balance between therapeutic efficacy and safety. Specifically, it might reduce the risk of opportunistic infections or other complications associated with broader immunosuppression, while still effectively controlling the pathogenic T-cell responses underlying autoimmune conditions. The advanced engineering of ZB-004, with its enhanced affinity and prolonged duration of action, is intended to optimize this targeted immunomodulatory effect, potentially leading to improved clinical outcomes for patients.

3. Clinical Development Program

3.1. Overview of Development for Autoimmune Diseases

ZB-004 is being strategically developed for the treatment of a spectrum of autoimmune diseases, capitalizing on its mechanism of inhibiting T-cell costimulation.[1] The foundational development work was conducted by Xencor, Inc. Following the establishment of its preclinical profile, Zenas BioPharma acquired the rights to ZB-004 and has since been responsible for its clinical advancement.[2] Zenas BioPharma initiated Investigational New Drug (IND)-enabling studies [5] and subsequently progressed ZB-004 into Phase 1 clinical trials.[2] To date, the most advanced stage of clinical development completed for ZB-004 is Phase 1.[2]

3.2. Focus: Phase 1 Single Ascending Dose Study (NCT05794516) in Healthy Volunteers

The cornerstone of ZB-004's early clinical evaluation is the Phase 1 Single Ascending Dose (SAD) study conducted in healthy volunteers.

• Study Identifiers:
• The primary clinical trial identifier is NCT05794516.[2]
• A secondary trial registry ID, ZB004-01-001, is also associated with this study.[17]
• Official Titles:
• The study is publicly registered with titles such as "A Single Ascending Dose (SAD) Study to Evaluate the Safety and Pharmacokinetics (PK) of ZB004 in Healthy Volunteers".[2]
• A more descriptive title, "A Phase 1 Single Ascending Dose Study to Evaluate the Safety and Pharmacokinetics of ZB004, a CTLA-4-Ig Fusion Protein Designed for Increased Binding Affinity and Extended Half-life, in Healthy Volunteers," was used in scientific presentations, such as at the American College of Rheumatology (ACR) meeting.[3]
• Sponsor: The study was sponsored by Zenas BioPharma LLC.[2]
• Study Objectives [3]:
• The primary objective was to evaluate the safety and tolerability of single ascending subcutaneous doses of ZB-004 in a healthy volunteer population. This is reflected in the primary outcome measure: the number of participants experiencing treatment-emergent adverse events (TEAEs).[17]
• Secondary objectives were comprehensive, aiming to:
• Characterize the pharmacokinetic (PK) profile of ZB-004, including parameters such as maximum observed serum concentration (Cmax), time to Cmax (Tmax), area under the concentration-time curve from time 0 extrapolated to infinity (AUCinf), and AUC from time 0 to the last quantifiable concentration (AUClast).[17]
• Assess the immunogenicity of ZB-004 by measuring the incidence and titers of anti-drug antibodies (ADA).
• Evaluate the pharmacodynamics (PD) of ZB-004, specifically focusing on target engagement (via CD86 receptor occupancy on peripheral blood cells) and functional T-cell modulation (indicated by ex vivo IL-2 inhibition).
• Study Design and Methodology [3]:
• Phase: Phase 1.
• Design: The study employed a robust randomized, double-blind, placebo-controlled, single ascending dose (SAD) design.
• Population: Participants were healthy male and female volunteers, aged between 18 and 55 years, inclusive. Key inclusion criteria stipulated a body weight of ≥50 kg for male participants and ≥45 kg for female participants, and a body mass index (BMI) ranging from 18 to 35 kg/m2. Participants were required to be in good health as determined by the Investigator. Female participants of child-bearing potential were required to agree to abstinence or use a highly effective form of contraception and refrain from egg donation until 6 months post-dose. Male participants were required to be surgically sterile or agree to use effective contraception and refrain from sperm donation for 6 months post-dose. Exclusion criteria included, but were not limited to, use of over-the-counter medications or vitamins/dietary supplements within 7 days of dosing (unless deemed non-interfering by the Investigator), clinically significant ECG abnormalities, positive tests for HIV, active hepatitis C or B, COVID-19 virus, or tuberculosis, any active infections within 30 days prior to dosing, a history of drug abuse within the previous 12 months, or excessive smoking or alcohol consumption.[17]
• Enrollment and Randomization: Each dosing cohort consisted of eight healthy volunteers. Within each cohort, participants were randomized in a 3:1 ratio to receive a single dose of either ZB-004 or a matching placebo.
• Administration Route: ZB-004 or placebo was administered via subcutaneous (SC) injection.
• Dose Levels: The study evaluated five single ascending dose levels of ZB-004: 3 mg, 12.5 mg, 50 mg, 125 mg, and 200 mg.
• Dose Escalation Procedure: The decision to escalate to the next higher dose cohort was made by a Safety Review Committee (SRC) after careful review of safety and tolerability data from the preceding cohort.
• Study Location: The trial was conducted at a single clinical research center: New Zealand Clinical Research.[3]
• Study Status: The study has been completed.[2]
• Key Dates (from ANZCTR record [17]):
• Ethics Submission Date: March 20, 2023.
• ANZCTR Registration Date: April 3, 2023.
• Actual Study Start Date: June 19, 2023.
• Actual Primary Completion Date: March 21, 2024.
• The record was last updated on the ANZCTR on August 15, 2024.

Table 2: Overview of Phase 1 SAD Clinical Trial (NCT05794516) Design

Feature	Details
Study Title	A Single Ascending Dose (SAD) Study to Evaluate the Safety and Pharmacokinetics (PK) of ZB004 in Healthy Volunteers
NCT Number	NCT05794516
Phase	Phase 1
Sponsor	Zenas BioPharma LLC
Design	Randomized, double-blind, placebo-controlled, single ascending dose
Population	Healthy Volunteers (N=40 total; 5 cohorts of 8 participants each, 3:1 active:placebo randomization per cohort), ages 18-55 years
Intervention	ZB-004, single subcutaneous (SC) injection
Dose Levels	3 mg, 12.5 mg, 50 mg, 125 mg, 200 mg
Control	Placebo, single subcutaneous (SC) injection
Location	New Zealand Clinical Research (single center)
Status	Completed
Primary Outcome Measures	Safety and Tolerability: Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs)
Secondary Outcome Measures	Pharmacokinetics (PK): Cmax, Tmax, AUCinf, AUClast, half-life<br>Immunogenicity: Anti-drug antibody (ADA) incidence and titer<br>Pharmacodynamics (PD): CD86 receptor occupancy, ex vivo IL-2 inhibition

This table consolidates the critical design elements of the first-in-human study for ZB-004, offering a structured and accessible overview of the trial's methodology and objectives. This framework is essential for interpreting the subsequent results and appreciating the scientific rigor of ZB-004's early clinical evaluation. The information is derived from multiple consistent sources.[2]

4. Phase 1 Clinical Trial (NCT05794516) Findings

The results from the Phase 1 single ascending dose study of ZB-004 in healthy volunteers have provided crucial initial data on its pharmacokinetic profile, pharmacodynamic activity, safety, and immunogenicity.[3]

4.1. Pharmacokinetics (PK)

The pharmacokinetic evaluation of ZB-004 yielded several key findings:

• Half-Life (t1/2​): ZB-004 demonstrated a notably extended terminal half-life, reported to be in the range of 8 to 18 days across the various doses studied. This prolonged half-life is a direct consequence of the Xtend™ Fc domain engineering (incorporating M428L and N434S amino acid substitutions), which is designed to enhance binding to the neonatal Fc receptor (FcRn). This interaction with FcRn salvages the protein from lysosomal degradation and recycles it back into circulation, thereby reducing its clearance rate and extending its persistence in the body. The clinically observed half-life of 8-18 days serves as a validation of this engineering strategy in humans, indicating that the Xtend™ technology effectively prolongs the circulation time of ZB-004. This duration is substantially longer than that typically observed for conventional IgG molecules or first-generation Fc fusion proteins that lack such half-life extension modifications, underscoring the success of this bioengineering approach.[3]
• Dose Proportionality and Target-Mediated Drug Disposition (TMDD): The study revealed that key pharmacokinetic parameters, such as the maximum observed serum concentration (Cmax) and the area under the concentration-time curve (AUC), exhibited a non-linear increase with escalating dose levels of ZB-004. This non-linear pharmacokinetic behavior is a strong indicator of target-mediated drug disposition (TMDD). TMDD occurs when a significant fraction of the administered drug binds with high affinity to its pharmacological target (in this case, CD80 and CD86 on antigen-presenting cells), and this binding process itself influences the drug's distribution and clearance dynamics. At lower doses, where target availability is a limiting factor, a larger proportion of the drug is bound and cleared via this target-mediated pathway. As doses increase and these target sites become progressively saturated, the clearance mechanisms become less dependent on target binding, and the pharmacokinetic behavior may transition towards linearity. The observation of TMDD for ZB-004 is pharmacologically significant as it provides in vivo evidence of high-affinity engagement with its intended targets. This characteristic is often observed with potent biologic therapies and is a positive indicator of strong target interaction within the physiological milieu.[3]
• Other PK Parameters: While the study assessed a range of standard pharmacokinetic parameters including Cmax, time to Cmax (Tmax), AUC from time 0 to infinity (AUCinf), and AUC from time 0 to the last quantifiable concentration (AUClast) [17], specific numerical values for these parameters beyond the general observation of non-linear dose-dependent increases were not detailed in the provided abstracts.

Table 3: Summary of Key Pharmacokinetic (PK) Parameters from NCT05794516

Parameter	Reported Value/Observation
Terminal Half-life (t1/2​)	8 – 18 days
Dose Proportionality (Cmax, AUC)	Non-linear increase with increasing dose
Target-Mediated Drug Disposition (TMDD)	Evidence of TMDD effect observed

This table succinctly presents the most critical pharmacokinetic findings for ZB-004 from its initial human study. The extended half-life is a key attribute supporting the potential for less frequent dosing, a significant advantage for chronic therapies. The observation of TMDD is pharmacologically important as it confirms potent target binding in vivo, a prerequisite for achieving the desired therapeutic effect. These data are crucial for designing subsequent multiple-dose studies and for understanding the dose-exposure-response relationships of ZB-004.[3]

4.2. Pharmacodynamics (PD)

The pharmacodynamic assessments provided direct evidence of ZB-004's biological activity and target engagement in healthy volunteers:

• Target Engagement - CD86 Receptor Occupancy (RO): The study demonstrated clear and dose-dependent engagement of ZB-004 with one of its intended targets on peripheral immune cells. Measurements of CD86 receptor occupancy in whole blood samples indicated that higher administered doses of ZB-004 resulted in a correspondingly greater percentage of CD86 receptor occupancy. This finding confirms that ZB-004 effectively reaches and binds to its target in the systemic circulation.[3]
• Functional Immunomodulation - Inhibition of IL-2 Production: Beyond simple target binding, ZB-004 demonstrated a functional consequence consistent with its proposed mechanism of action. Pharmacodynamic activity was evaluated by measuring the inhibition of Interleukin-2 (IL-2) production in whole blood samples that were stimulated ex vivo. ZB-004 treatment resulted in the inhibition of IL-2 production across all dose cohorts tested. IL-2 is a critical cytokine produced by activated T-cells and plays a central role in promoting T-cell proliferation, survival, and effector functions. Its inhibition is a key indicator of reduced T-cell activation.[3]

The pharmacodynamic data from this Phase 1 study are particularly significant. They establish a clear link between the administration of ZB-004, its engagement with the cell-surface target CD86 in a dose-responsive manner, and a consequent functional immunomodulatory effect (inhibition of IL-2 production). CD86 is a crucial ligand for the CD28 costimulatory receptor on T-cells. By occupying CD86, ZB-004 effectively blocks the CD28-mediated costimulatory signal necessary for full T-cell activation, which in turn leads to reduced IL-2 synthesis. This demonstration of a clear pharmacokinetic/pharmacodynamic (PK/PD) relationship in an early-phase human study provides strong validation for the drug's intended mechanism of action and is instrumental in guiding dose selection for subsequent therapeutic trials in patient populations.

Table 4: Summary of Key Pharmacodynamic (PD) Markers from NCT05794516

PD Marker	Key Finding
CD86 Receptor Occupancy (RO) in whole blood	Clear target engagement; dose-dependent increase in %CD86 RO.
Ex vivo stimulated IL-2 production	Inhibition of IL-2 production observed in all dose cohorts.

This table highlights that ZB-004 is not merely present in the systemic circulation (as shown by PK data) but is also biologically active at its intended molecular target. The ability to demonstrate both target engagement and a relevant downstream functional effect in a Phase 1 study is a critical milestone. It significantly de-risks further development by providing confidence in the drug's proposed mechanism of action and its potential to effectively modulate immune responses in individuals with autoimmune diseases.[3]

4.3. Safety and Tolerability

The evaluation of safety and tolerability was a primary objective of the NCT05794516 study.

• ZB-004 was reported to be safe and well-tolerated when administered as single subcutaneous doses across the entire range studied, from 3 mg up to 200 mg.[3]
• No significant or unexpected safety signals were identified during the course of the study.[3]
• The adverse events (AEs) that were observed were generally mild in severity. Their nature and incidence were consistent with those typically expected in a healthy volunteer population participating in a clinical trial involving subcutaneous injections (e.g., transient injection site reactions such as redness or mild discomfort).[3]
• Crucially, no serious adverse events (SAEs) were reported in any of the dose cohorts throughout the study.[3]
• The primary outcome measure of the trial, which focused on the number of participants experiencing TEAEs [17], supported an overall favorable safety profile for ZB-004 in this healthy volunteer setting.

Table 5: Summary of Safety and Tolerability Findings from NCT05794516

Safety Aspect	Finding
Overall Tolerability	Well-tolerated at all single SC doses studied (up to 200 mg).
Adverse Events (AEs)	Mild; consistent with expectations in healthy volunteers; no new signals.
Serious Adverse Events (SAEs)	None observed.
Key Safety Conclusion	Favorable safety and tolerability profile in healthy volunteers.

Establishing a robust safety and tolerability profile in Phase 1 is a fundamental prerequisite for the continued development of any investigational therapeutic. The findings for ZB-004, as summarized in this table, are positive, indicating that the drug, at the single doses tested, did not elicit undue safety concerns in healthy individuals. This favorable outcome is critical for supporting the progression of ZB-004 into studies involving patient populations with autoimmune diseases, where the risk-benefit assessment will be further refined.[3]

4.4. Immunogenicity

The potential for ZB-004 to elicit an immune response in the form of anti-drug antibodies (ADAs) was assessed as a secondary objective.

• Analyses for ADAs were conducted on samples from study participants.[3]
• An noteworthy trend emerged from these analyses: there was an observed lowering of both the incidence (the proportion of subjects who developed ADAs) and the titer values (the concentration of ADAs) of anti-ZB-004 antibodies as the administered dose of ZB-004 increased.[3]
• This inverse relationship between ZB-004 dose and ADA formation was interpreted as being consistent with the known immunosuppressive mechanism of action of ZB-004, and CTLA-4-Ig therapies in general.[3]

The observation that higher doses of an immunomodulatory agent like ZB-004 are associated with a reduction in its own immunogenicity is a significant and highly favorable finding. Typically, increased exposure to a therapeutic protein might be anticipated to elevate the risk of an immune response against it. However, in the case of ZB-004, its primary pharmacological activity—the inhibition of T-cell costimulation—is likely dampening the T-cell dependent immune response that would be necessary for the generation of high-affinity ADAs against the ZB-004 protein itself. As higher doses of ZB-004 achieve greater systemic immunosuppression, this effect appears to extend to mitigating the immune system's ability to recognize and mount a response to ZB-004 as a foreign antigen. This characteristic is particularly desirable for a biologic therapeutic intended for chronic administration in the context of autoimmune diseases. A reduced risk of developing clinically relevant ADAs could translate to more sustained efficacy over time, a lower likelihood of altered pharmacokinetic profiles due to ADA binding, and a diminished potential for ADA-mediated hypersensitivity reactions or other adverse events. This favorable immunogenicity trend, if maintained in patient populations, would represent a substantial advantage for ZB-004.

5. Intellectual Property Landscape

The development of ZB-004 is underpinned by a robust intellectual property (IP) framework, primarily stemming from Xencor's proprietary XmAb® antibody engineering technologies.

• Xtend™ Fc Technology: A core component of ZB-004's design is the Xtend™ Fc domain, which incorporates specific amino acid substitutions (M428L/N434S) to enhance binding to the neonatal Fc receptor (FcRn) and thereby extend the drug's plasma half-life.[3] Xencor possesses a significant patent portfolio covering its Fc engineering technologies, including various Fc variants with modulated FcRn binding characteristics designed for half-life extension.[11] Patents such as US9884902B2 [12] and US10793632B2 [13] describe Fc variants engineered for altered FcRn interactions, providing a foundational IP basis for the Xtend™ technology used in ZB-004.
• CTLA-4 ECD Modifications: The bioengineering of ZB-004 also includes specific amino acid substitutions within the CTLA-4 extracellular domain (ECD), aimed at increasing its binding affinity to the target ligands CD80 and CD86.[3] Xencor's patent US9884902B2 [12] explicitly claims CTLA-4 variants with modified ECDs that exhibit enhanced affinity, and also covers fusion proteins comprising these modified CTLA-4 ECDs linked to Fc domains (including those with half-life extension mutations). This patent likely provides IP coverage for the ECD engineering aspect of ZB-004.
• Composition of Matter and Methods of Use: The unique combination of these engineered CTLA-4 ECD variants with the specific Xtend™ Fc domain (M428L/N434S on a hybrid IgG1/2 backbone) in the ZB-004 molecule would constitute a novel composition of matter. This specific molecular entity, along with its methods of use for treating autoimmune diseases, is expected to be protected by dedicated patents. The licensing agreement between Xencor and Zenas BioPharma for ZB-004 (XmAb10717) would encompass the transfer or licensing of these relevant patent rights.[5]

The multi-faceted bioengineering strategy employed in ZB-004, which integrates proprietary modifications to both the ligand-binding CTLA-4 ECD and the pharmacokinetic-modulating Fc domain (Xtend™ technology), results in a highly differentiated molecular entity. This intricate design, combining enhanced target affinity with an extended half-life, is likely protected by a layered and robust intellectual property portfolio. Xencor's established expertise and comprehensive patent estate in the field of Fc engineering and antibody optimization [11] form a strong foundation for this IP position. Zenas BioPharma, through its licensing agreement, leverages this existing IP to secure exclusive rights for the continued development and commercialization of ZB-004. This strong IP protection is crucial for attracting investment, supporting long-term development efforts, and ultimately, ensuring market exclusivity for ZB-004 should it achieve regulatory approval.

6. Discussion and Future Perspectives

6.1. Interpretation of Phase 1 Findings

The Phase 1 single ascending dose study (NCT05794516) of ZB-004 in healthy volunteers successfully met its predefined objectives. The data clearly demonstrated that ZB-004 is safe and well-tolerated at subcutaneous doses up to 200 mg.[3] The pharmacokinetic analysis confirmed the attainment of an extended plasma half-life, ranging from 8 to 18 days, which aligns with the intended design benefit of the Xtend™ Fc technology and supports the potential for less frequent dosing regimens in a clinical setting. Furthermore, the observation of target-mediated drug disposition (TMDD) provided in vivo evidence of potent and specific binding of ZB-004 to its targets, CD80 and CD86.[3]

Pharmacodynamically, the study yielded compelling results. Clear, dose-dependent target engagement was demonstrated through measurements of CD86 receptor occupancy. This was complemented by evidence of functional immunomodulation, as indicated by the inhibition of ex vivo stimulated IL-2 production across all dose cohorts.[3] These PD findings confirm that ZB-004 not only reaches and binds its target but also elicits a biological response consistent with its proposed mechanism of T-cell costimulation blockade. The immunogenicity profile observed was also favorable, with an intriguing trend towards lower incidence and titers of anti-drug antibodies (ADAs) at higher doses of ZB-004, potentially attributable to the drug's own immunosuppressive effects.[3]

6.2. Implications of Enhanced Affinity and Extended Half-Life for Clinical Utility

The bioengineered attributes of ZB-004—enhanced affinity for CD80/CD86 and an extended circulating half-life—carry significant implications for its potential clinical utility in autoimmune diseases:

• Enhanced Affinity: The modifications in the CTLA-4 ECD, designed to increase binding affinity to CD80 and CD86, may translate to greater therapeutic potency. This could allow for the use of lower therapeutic doses to achieve the desired level of T-cell costimulation blockade, potentially improving the benefit-risk profile. Alternatively, at comparable doses to existing therapies, the higher affinity might lead to more complete or sustained target saturation, which could be particularly beneficial in autoimmune conditions characterized by high levels of APC activation and CD80/CD86 expression, or in patient populations who are refractory to standard treatments.
• Extended Half-Life: The incorporation of Xencor's Xtend™ Fc technology is a cornerstone of ZB-004's differentiation strategy. The clinically observed half-life of 8 to 18 days supports the feasibility of dosing regimens that are significantly less frequent than those required for many current biologic therapies, such as daily or weekly administrations. The potential for bi-weekly or even monthly subcutaneous injections would represent a substantial improvement in patient convenience and could markedly reduce the overall treatment burden associated with managing chronic autoimmune diseases. Such convenience is often a strong driver of patient adherence to long-term therapy, which is crucial for optimal disease control and outcomes.

The combination of these engineered improvements—potentially higher potency stemming from enhanced target affinity and a markedly improved dosing schedule enabled by the extended half-life—positions ZB-004 as a potentially differentiated, next-generation CTLA-4-Ig therapeutic. In the competitive landscape of autoimmune disease treatments, new entrants must offer clear and tangible advantages over existing standards of care. Abatacept, the first-generation CTLA-4-Ig, has established the clinical utility of this mechanism but typically requires weekly subcutaneous injections or monthly intravenous infusions. A therapy like ZB-004, if its efficacy and safety are confirmed in patient populations, could offer a similar or potentially improved therapeutic effect with a much more patient-friendly and convenient dosing regimen. This dual advantage of potentially superior pharmacology and enhanced convenience could make ZB-004 a preferred therapeutic option for both patients and prescribing clinicians in the future.

6.3. Potential in Autoimmune Diseases and Development by Zenas BioPharma

The fundamental mechanism of T-cell costimulation blockade via CTLA-4-Ig fusion proteins is a clinically validated therapeutic strategy for a range of T-cell-mediated autoimmune diseases. Conditions such as rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis have seen significant treatment advances with the use of abatacept.[7] The broad applicability of this mechanism suggests that ZB-004 could also have therapeutic potential across a similar spectrum of autoimmune disorders.

Zenas BioPharma, the current developer of ZB-004, has a clear strategic focus on immunology and the development of therapies for autoimmune diseases. This is evident from its broader pipeline, which includes other immunomodulatory candidates such as obexelimab (a bifunctional antibody targeting CD19 and FcγRIIb) and ZB002 (an anti-TNFα therapy).[2] While the specific autoimmune indications that Zenas BioPharma will prioritize for ZB-004 development beyond the general classification of "Autoimmune Diseases" [2] are not explicitly detailed in the currently available information, the company's overall focus and the drug's mechanism of action suggest a wide range of potential applications. The selection of lead indications for Phase 2 and Phase 3 development will likely be a strategic decision informed by several factors, including the strength of the scientific rationale for CTLA-4 pathway involvement in specific diseases, the magnitude of unmet medical need, the existing standard of care and competitive landscape in those indications, and an assessment of where ZB-004's potentially differentiated profile (e.g., less frequent subcutaneous dosing, potentially higher potency) might offer the most compelling clinical benefit and market opportunity.

6.4. Considerations for Future Clinical Development

The positive outcomes from the Phase 1 SAD study in healthy volunteers provide a strong rationale for advancing ZB-004 into further clinical development, specifically into Phase 2 proof-of-concept studies in patient populations with selected autoimmune diseases. Several key considerations will shape this future development:

• Dose and Regimen Selection for Phase 2: The selection of optimal doses and dosing regimens for Phase 2 trials will be a critical step. This decision will be heavily informed by comprehensive pharmacokinetic/pharmacodynamic (PK/PD) modeling using the data generated in the Phase 1 study. The observed TMDD, in particular, necessitates careful consideration to ensure that the chosen regimen achieves and maintains adequate target saturation (CD80/CD86 blockade) to elicit a therapeutic effect, while also capitalizing on the convenience of less frequent dosing afforded by the extended half-life. Multiple ascending dose (MAD) studies in healthy volunteers or patients may also be conducted to further refine the dosing strategy.
• Indication Prioritization: Zenas BioPharma will need to strategically prioritize which autoimmune indications to pursue initially. This decision will likely involve evaluating the strength of the biological rationale for targeting the CTLA-4 pathway in various diseases, the level of unmet medical need, the existing therapeutic landscape and standards of care, and the potential for ZB-004's unique attributes (e.g., enhanced affinity, extended half-life, subcutaneous administration) to provide a meaningful clinical advantage.
• Long-Term Safety and Immunogenicity: While the Phase 1 data are encouraging, the long-term safety and immunogenicity of ZB-004 will need to be rigorously assessed in larger and more diverse patient populations over extended treatment durations. This will be a key focus of Phase 2 and Phase 3 trials. The favorable early immunogenicity trend observed in healthy volunteers (lower ADA incidence/titers at higher doses) will require confirmation in chronically treated patients.
• Biomarker Strategy: The incorporation of a robust biomarker strategy into future clinical trials could significantly enhance the efficiency of development. This might include biomarkers to identify patient subpopulations most likely to respond favorably to ZB-004, or biomarkers to monitor target engagement, biological response, and disease activity throughout the course of treatment.

While the robust Phase 1 data have significantly de-risked the early development of ZB-004 from the perspectives of safety, pharmacokinetics, and confirmation of its mechanism of action, the path to demonstrating definitive clinical efficacy in specific autoimmune diseases remains a challenging endeavor. Autoimmune diseases are often complex and heterogeneous, and patient responses to immunomodulatory therapies can vary considerably. Translating the favorable profile observed in healthy volunteers into clinically meaningful improvements in disease activity, patient-reported outcomes, and overall quality of life in specific patient populations will be the next major developmental hurdle. The competitive environment within the autoimmune therapeutic space is intense, with numerous existing and emerging therapies. The ultimate success of ZB-004 will hinge on its ability to demonstrate a clear and compelling clinical advantage—whether in terms of superior efficacy, an improved safety profile, or enhanced patient convenience and adherence—in well-chosen indications. Nevertheless, the strong foundational science, meticulous bioengineering, and positive early clinical data for ZB-004 provide a promising basis for its continued development by Zenas BioPharma.

7. Conclusion

ZB-004 (XmAb10717) is a rationally designed, second-generation CTLA-4-Ig fusion protein that incorporates advanced bioengineering features aimed at enhancing its therapeutic properties for the treatment of autoimmune diseases. Key among these features are modifications to the CTLA-4 extracellular domain for increased binding affinity to its targets (CD80/CD86) and the incorporation of Xencor's Xtend™ Fc technology (M428L/N434S substitutions) to achieve a significantly extended pharmacokinetic half-life.

The recently completed Phase 1 single ascending dose clinical trial (NCT05794516) in healthy volunteers has provided critical initial validation of ZB-004's profile. The study demonstrated that ZB-004 is safe and well-tolerated at subcutaneous doses up to 200 mg. Pharmacokinetic analyses confirmed the intended extended half-life of 8 to 18 days, supporting the potential for less frequent dosing regimens, and revealed target-mediated drug disposition indicative of potent in vivo target binding. Furthermore, pharmacodynamic assessments provided clear evidence of dose-dependent target engagement, as measured by CD86 receptor occupancy, and functional immunomodulation, demonstrated by the inhibition of ex vivo stimulated IL-2 production. The immunogenicity profile of ZB-004 also appears favorable, with an observed trend towards lower anti-drug antibody formation at higher doses, possibly due to the drug's inherent immunosuppressive activity.

Collectively, these Phase 1 findings are highly encouraging and provide a strong foundation for the continued clinical development of ZB-004 by Zenas BioPharma. ZB-004 stands as a promising therapeutic candidate with the potential to offer an improved clinical profile, including enhanced patient convenience, compared to existing therapies for a range of autoimmune diseases. Future clinical studies in patient populations will be essential to definitively establish its efficacy and long-term safety in specific autoimmune indications.

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