For what indications are Immune stimulating antibody conjugate (ISAC) being investigated?

Introduction to Immune Stimulating Antibody Conjugates (ISACs)

Definition and Mechanism of Action
Immune stimulating antibody conjugates (ISACs) are an emerging class of therapeutic agents that combine a targeting antibody with an immune activator. In essence, these conjugates use the specificity of an antibody to bind selectively to antigens—often overexpressed on tumor cells—and deliver a potent immune stimulant directly into the tumor microenvironment. The immune activator portion can be in the form of small molecules, agonists of innate immune receptors (such as TLR7/8 agonists or STING agonists), or other immunomodulatory compounds. This dual-function mechanism ultimately aims to both localize the therapeutic action and induce a robust immune response. By activating innate immune cells (such as dendritic cells, macrophages, and natural killer cells) as well as modulating adaptive immunity, ISACs help to transform an immune “cold” tumor into one that is “hot” and prone to immune-mediated destruction.

Overview of ISACs in Immunotherapy
In the realm of immunotherapy, conventional approaches such as immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by taking the brakes off the immune system. ISACs differentiate themselves by not merely releasing the brakes but by actively “stepping on the gas” of the immune system. They work by a “payload–targeting” strategy: the antibody binds to a specific cell surface marker, thereby concentrating the immune stimulant payload at the disease site. Additionally, because the immune stimulatory agents are typically linked via a non-cleavable linker, their release is confined to the target tissue, minimizing systemic toxicity. These attributes make ISACs a promising modality, synergistically combining the specificity of antibody targeting with the potency of immune activators to produce both innate and adaptive immune responses.

Current Indications for ISACs

Oncology
The most advanced and extensively investigated application of ISACs is in oncology. Almost all of the current ISAC candidates described in the synapse-sourced literature are developed primarily for the treatment of neoplastic diseases. For example, one candidate—BPT-567 by Bright Peak Therapeutics AG—is designed for neoplasms and targets the interleukin-18 receptor 1 (IL18R1) in combination with PD-1 inhibition, thereby harnessing both an agonist mechanism (to stimulate an innate immune response) and an inhibitor mechanism (to prevent immune suppression).

Additionally, GeneQuantum Healthcare’s candidate, GQ-1007, is characterized as an immune stimulating antibody conjugate by targeting HER2. Its dual mechanism—combining HER2 antagonism with immunogenetic stimulation—represents an innovative approach to treat HER2-positive tumors, which include subtypes of breast cancer, gastric cancer, and other solid tumors that overexpress HER2.

Innovent Biologics (Suzhou) Co. Ltd. developed IBI-3007, a candidate ISAC that targets complex receptor structures such as TLR7 x TLR8 and Trop-2. Trop-2 is frequently overexpressed in a variety of solid tumors, and by simultaneously engaging TLRs and inhibiting Trop-2, the conjugate can stimulate immune responses while directly interfering with tumor growth signals.

Other ISAC candidates are designed to target tumor-specific antigens or receptors that are coupled with an immune agonist payload such as STING agonists. For instance, the anti-HER2 antibody STING agonist conjugate from Daiichi Sankyo is currently investigated in preclinical models and is aimed at triggering robust antitumor immune responses by coupling HER2 targeting with direct stimulation of the STING pathway. Similar preclinical agents from Mersana Therapeutics (XMT-2175 and XMT-2068) and F-Star Therapeutics (STING agonist ADC) also focus on harnessing innate immune activation through the STING pathway, which is critical for recognizing cytosolic DNA and initiating an inflammatory response that sharpens antitumor immunity.

Another noteworthy ISAC candidate is from Bolt Biotherapeutics, which has developed an anti-PDL1 immune stimulating antibody conjugate. This agent, still under preclinical investigation, is intended to block the inhibitory signals of PDL1 while simultaneously delivering immune stimulants (such as TLR agonists) to activate T lymphocytes and induce antibody-dependent cellular cytotoxicity (ADCC). In addition, the candidate IgG(XE114)-ValCit-PABC-R848 developed by the University of Milan targets the CAIX antigen in conjunction with TLR7/8 stimulation, thereby further demonstrating how ISACs can be tailored to the specific immunological profile of different tumors.

The majority of these agents target “neoplasms” as a disease area. The rationale behind this focus is that tumors often develop mechanisms to evade immune detection, and by locally intensifying immune responses through ISACs, it is possible to overcome intrinsic resistance. Moreover, ISACs provide the added advantage of recruiting multiple arms of the immune system, potentially leading to durable responses and long-term immunological memory which could prevent relapse—a critical need given that many responders to conventional therapies eventually develop resistance.

Autoimmune Diseases
While the primary indication for ISACs as described in the current synapse literature is oncology, there is a broader conceptual framework within immunotherapy wherein strategies that modulate immune activation may also be repurposed for autoimmune diseases. However, in the context of ISAC development, the immune stimulation conferred by these conjugates is purposely directed to override an immunosuppressive tumor microenvironment. In contrast, autoimmune diseases involve an overactive or misdirected immune system. Thus, the mechanisms underlying ISACs are not optimally suited for the treatment of autoimmune diseases without significant modification, because stimulating the immune system further in a context where it is already hyperactive could exacerbate pathological immune responses.

That said, research in related fields has demonstrated that immune modulation can sometimes be fine-tuned to address autoimmune disorders, such as by inducing tolerance through targeted immune regulation. Although current ISAC investigations as provided in the synapse references are almost exclusively focused on neoplasms, there exists a potential for future adaptation—whereby the targeted delivery of specific immune agonists could be counterbalanced by co-administering modulators of autoimmunity—to treat autoimmune conditions. However, at present, there is no direct clinical trial evidence from the synapse references indicating active ISAC investigation in autoimmune disorders.

Infectious Diseases
Immunotherapies based on stimulating innate and adaptive immune responses have also been explored in the field of infectious diseases. The concept of directing immune responses to sites of infection or to pathogen-infected cells shares mechanistic similarities with how ISACs operate in oncology. In theory, the precision targeting of immune stimulants via antigen-specific antibodies could be applied to infectious pathogens by directing effector immune responses to the site of infection. Nonetheless, the current wave of ISAC candidates, as reflected in the synapse-sourced literature, has not yet been advanced into clinical trials specifically for infectious diseases. Most of the investigative work remains focused on oncology indications.

That said, the underlying technology and design principles used for developing ISACs have the potential for extension into infectious disease indications in the future. For example, targeting pathogen-specific antigens in conjunction with the delivery of immune stimulatory signals might increase pathogen clearance and improve outcomes in chronic or resistant infections. However, significant preclinical work and subsequent clinical validation would be necessary to translate this concept into a viable therapeutic strategy.

Research and Clinical Trials

Ongoing Clinical Trials
Several ISAC candidates have advanced into early-phase clinical trials, particularly for oncology indications. For example, in the realm of neoplasms, Boltbody ISACs are a prominent example. As reported in recent news articles, Bolt Biotherapeutics has been investigating its lead candidate BDC-1001 in a Phase I/II study. Preliminary data from these studies indicate early signs of clinical activity, such as stable disease and partial responses in patients with HER2-expressing tumors, including those with low HER2 expression. Moreover, the studies suggest that ISAC-mediated treatment may yield durable treatment responses through the stimulation of both innate myeloid cells and adaptive T lymphocytes.

In a Phase I/IIa trial context, updated patient response data have been shared in international meetings, such as the Society for Immunotherapy of Cancer (SITC) Meeting. These trials typically evaluate not only the tolerability and safety profile but also pharmacokinetic and pharmacodynamic biomarkers to confirm the mechanism of action in humans, thereby reinforcing the hypothesis that localized immune stimulation can generate systemic anti-tumor immunity.

Other ISAC candidates have been noted to be in early clinical development or in the IND (Investigational New Drug) application stage, which is the case for IBI-3007 from Innovent Biologics and several STING agonist conjugates from companies such as Daiichi Sankyo and Mersana Therapeutics. The advancement into clinical trials demonstrates the strong interest in assessing whether the preclinical successes in immunostimulation and tumor eradication can be replicated in the more complex human system.

Preclinical Studies
Preclinical research forms the backbone of ISAC development. Extensive in vitro and in vivo studies have been conducted to ascertain the efficacy, safety, and optimal dosing of ISAC molecules. In these studies, researchers have tested various conjugate designs with different immune stimulatory payloads across a range of tumor models. For instance, the candidate IgG(XE114)-ValCit-PABC-R848 from the University of Milan has been investigated in preclinical models to understand its capacity to inhibit CAIX and stimulate TLR7/8 pathways, translating into tumor regression in relevant models.

Preclinical investigations have also employed animal models to assess biodistribution, immune cell recruitment, cytokine release profiles, and potential off-target toxicities. These studies allow researchers to fine-tune linker chemistries, ensure stable conjugate design, and optimize the balance between efficacy and safety. Additionally, many preclinical experiments utilize surrogate endpoints such as tumor volume reduction, survival curves, and immunohistochemical assessments of immune cell infiltration in the tumor microenvironment to wind down the efficacy before moving into human trials.

Furthermore, preclinical studies have explored combination strategies where ISACs are used alongside other therapeutic modalities, such as ICIs, targeted therapies, or conventional chemotherapy. The rationale is that the potent immune activation by ISACs may synergize with other treatment approaches to overcome resistance and improve clinical outcomes. Although these combination approaches are currently more experimental in nature, they offer an avenue for broadening the indications and enhancing the overall benefit of ISAC-based therapies.

Challenges and Future Directions

Current Challenges in ISAC Development
Despite promising results, several challenges remain in the development and clinical translation of ISACs. One major challenge is the optimization of the therapeutic window. The potent immune stimulatory effect needs to be carefully balanced to avoid excessive systemic inflammation or immune-related adverse events (irAEs), which have been observed with other immunotherapies such as checkpoint inhibitors. The risk of inducing cytokine release syndrome or off-target immune activation is significant and must be monitored both in the preclinical and clinical phases.

Another challenge is the determination of optimal dosing and administration schedules. Preclinical studies provide insights into dose-dependency, but translating these findings into human dosing regimens is complicated by interspecies differences in pharmacokinetics and immunological responses. Furthermore, the selection of biomarkers to assess the immune activation in the tumor microenvironment and to predict durable responses is an ongoing area of research. Validated biomarkers could not only help in patient selection but also in adjusting dosing regimens during treatment.

The design and engineering of the molecular conjugate itself also pose challenges. The stability of the linker, the specificity of the targeting antibody, and the bioactivity of the immune stimulant must be preserved while ensuring manufacturability and reproducibility under GMP conditions. Many of the candidates are in early or preclinical stages, and scale-up manufacturing issues or unexpected immunogenicity may limit their clinical implementation if not resolved early in the development process.

Finally, the heterogeneity of tumors remains a significant hurdle. Tumors can vary widely in their antigen expression profiles, immune cell infiltrates, and resistance mechanisms. This diversity means that a “one-size-fits-all” ISAC may not be effective across all tumors. Personalizing these conjugates—either by selecting appropriate antibody targets for individual patients or by tailoring the payloads to match the immunobiology of each tumor—represents both a challenge and a promising future direction.

Future Research Directions and Potential Indications
Looking ahead, future research directions for ISACs are both exciting and multifaceted. In oncology, one key research strategy is the combination of ISACs with other therapeutic modalities. Synergistic regimens that pair ISACs with ICIs, targeted therapies, or even adoptive cell therapies could potentially yield superior clinical outcomes by attacking tumors from multiple immunological angles. Ongoing and planned clinical trials are already exploring these combinations, and future studies might further refine patient selection criteria using advanced biomarker panels and genomic profiling.

On the technological side, next-generation linker chemistries and novel immune stimulatory payloads are under investigation. These improvements aim to maximize the intratumoral concentration of the immune stimulant while minimizing systemic exposure. With advances in nanotechnology and controlled-release formulations, there is potential to further refine the delivery mechanism and improve both efficacy and safety profiles.

Although current investigations largely focus on oncology, the underlying principles of ISAC technology could be repurposed for other indications in the future. For instance, in infectious diseases, targeted delivery of immune stimulants could enhance pathogen clearance by directing the immune system to specific infected cells. This approach might be particularly effective against chronic infections or in scenarios where the pathogen employs immune evasion strategies similar to tumors. While no current trials directly target infectious diseases with ISACs, the modular nature of these conjugates suggests that with appropriate modifications (such as changing the antibody to one that targets pathogen-specific antigens), such applications could be realized in the future.

In the realm of autoimmune diseases, although it appears counterintuitive to further stimulate an already overactive immune system, lessons learned from immune modulation and tolerance induction might eventually inform the design of “inverse” conjugates. These might incorporate immune regulatory molecules to re-establish tolerance in diseases such as rheumatoid arthritis or systemic lupus erythematosus. However, such approaches would require a fundamental re-engineering of the ISAC concept, and at present, the focus remains predominantly on antitumor applications.

Moreover, advanced preclinical models using patient-derived xenografts, humanized mouse models, and even organoids derived from induced pluripotent stem cells (iPSCs) are being developed. These models can better recapitulate human tumor biology and the complexity of the immune response, thereby providing more accurate predictions of clinical outcomes. Further integration of systems biology and bioinformatics with preclinical studies may also help identify optimal combination strategies and new biomarkers to facilitate personalized ISAC therapies.

Lastly, future research will likely focus on overcoming manufacturing and regulatory hurdles. Establishing robust manufacturing protocols and quality control measures is imperative for the clinical success of ISACs. Regulatory agencies will demand consistent safety and efficacy profiles, and collaborative efforts among industry, academia, and regulatory bodies will play a key role in the successful translation of this technology.

Conclusion
In summary, immune stimulating antibody conjugates (ISACs) represent a novel and promising modality in immunotherapy that combines the exquisite targeting ability of antibodies with the potent immune-activating properties of immune stimulants. Current ISAC research is predominantly focused on oncology, where these agents are being investigated for a wide range of neoplasms. Examples include candidates targeting IL18R1/PD-1, HER2, TLR7/8, STING, and PDL1, among others, aiming to activate both innate and adaptive immune responses to eradicate tumor cells. While the primary focus is on cancer treatment, the underlying technology presents future opportunities for extension into infectious diseases—where targeted immune activation could help clear chronic infections—and even into autoimmune diseases, though the latter would require re-engineering the approach to avoid exacerbating immune activity.

Ongoing clinical trials, such as those being conducted by Bolt Biotherapeutics with their Boltbody ISACs, are providing early indications of efficacy and tolerability in patients with advanced, HER2-expressing solid tumors. Preclinical studies have been instrumental in optimizing these conjugates by fine-tuning antibody specificity, immune stimulant potency, dosing regimens, and linker stability. Nonetheless, challenges remain in translating robust preclinical outcomes into consistent clinical success. These challenges include the optimization of the therapeutic window to avoid adverse immune reactions, the identification of reliable biomarkers for patient stratification, and ensuring manufacturing consistency and regulatory compliance.

Looking forward, future research directions for ISACs are likely to involve combination therapy strategies in oncology, integration of advanced drug delivery systems, and the possible exploration of indications beyond cancer. With continued advances in preclinical modeling, bioinformatics, and translational research, the next generation of ISACs could further refine personalized treatment approaches, ultimately enhancing clinical outcomes and expanding the therapeutic reach of immune-based interventions.

In conclusion, while the current indications for ISACs are predominantly within oncology owing to the direct need to overcome tumor immune evasion, the foundational principles of ISAC design hold promise for future applications in infectious diseases and potentially in autoimmune disorders through innovative adaptations. The ongoing evolution of ISAC candidates from the bench to early clinical assessments underscores the dynamic nature of this field. Addressing the existing challenges through intensified research efforts and technological enhancements will be essential to unlock the full potential of ISACs as a transformative tool in precision immunotherapy.