What are the different types of drugs available for Immune stimulating antibody conjugate (ISAC)?

Introduction to Immune Stimulating Antibody Conjugate (ISAC)

Definition and Mechanism
Immune Stimulating Antibody Conjugates (ISACs) are an emerging class of biopharmaceuticals that combine the exquisite target‐specificity of monoclonal antibodies with immune stimulating payloads. Unlike conventional antibody–drug conjugates (ADCs) that carry cytotoxic agents for direct tumor cell killing, ISACs are designed to “re-educate” the tumor microenvironment by delivering immune stimulatory molecules—such as Toll-like receptor (TLR) agonists, cytokines, or STING agonists—directly to tumor sites. This mechanism not only facilitates the targeted activation of the immune system against malignant cells but also helps to initiate and sustain antitumor immunity by recruiting and activating innate immune cells, antigen-presenting cells, and T lymphocytes. The immune stimulating payload is conjugated to the antibody with optimized linkers that ensure the payload remains inactive in circulation and is released at the desired location within the tumor microenvironment, thereby minimizing systemic immunotoxicity while enhancing local immune activation.

Historical Development and Current Status
The concept of integrating immune stimulatory functions into antibody therapeutics evolved from early ADC technology, which originally focused on cytotoxic payloads for direct cell killing. As the limitations of traditional ADCs became apparent—particularly in terms of off-target toxicity and the emergence of resistance—researchers moved towards the development of next-generation conjugates that could harness the patient’s own immune system. Over the past decade, several companies have spearheaded ISAC development. For instance, Tallac Therapeutics, in collaboration with ALX Oncology Inc., has advanced ALTA-002, a Phase 1 immune stimulating antibody conjugate targeting TLR9. Additionally, preclinical abstracts such as those presented at AACR 2023 and AACR 2024 have introduced PD1-IL18 conjugates (e.g., BPT567) that preferentially activate intratumoral effector T cells, illustrating the paradigm shift from direct cytotoxicity to immune modulation. Today, ISACs stand at the intersection of immunotherapy and targeted therapy, providing versatile options that can be combined with other immunomodulatory agents to overcome immune suppression in cancers.

Types of Drugs Used in ISAC

Classification of Drugs
The drugs used as payloads in ISACs can be broadly classified based on their molecular targets, receptor engagement, and downstream immune stimulating functions. The principal classes of drugs available for use in ISACs include:

1. TLR Agonists
Toll-like receptor agonists, particularly TLR9 agonists, are among the most well-known payload types. These molecules leverage innate immune signaling by mimicking pathogen-associated molecular patterns (PAMPs) to trigger dendritic cell activation and subsequent T-cell priming. For example, ALTA-002 is a TLR9 agonist-based ISAC developed by Tallac Therapeutics and ALX Oncology Inc. and is currently in Phase 1 development.

2. Cytokine-Based Payloads (Immunocytokines)
Cytokines such as interleukin-18 (IL-18) have been integrated into ISAC platforms to directly stimulate immune cell proliferation and cytotoxic activity. PD1-IL18 conjugates, like BPT567, are designed to specifically target PD-1 positive T cells within the tumor. By delivering IL-18 in a targeted manner, these conjugates enhance effector T-cell responses while simultaneously mitigating the systemic toxicity typically associated with recombinant cytokine therapy.

3. STING Agonists
With the rise of interest in the STING (Stimulator of Interferon Genes) pathway for cancer immunotherapy, STING agonists have been explored as payloads in ISACs. These molecules work by activating innate immune responses leading to type I interferon production, thereby inducing a robust antitumor immune response. Takeda Pharmaceutical and other entities have been researching CCR2-targeted STING agonists, such as TAK-500, which, while sometimes developed in an ADC context, share mechanistic similarities with ISACs in their ability to locally stimulate immune responses.

4. Other Immune Modulators
Beyond the classical categories mentioned above, researchers are also investigating other small molecule immune modulators (for example, new chemical entities that may target receptors such as NOD-like receptors, other TLR isoforms beyond TLR9, or even non-traditional targets) as ISAC payloads. Some preclinical studies have also examined payloads that modulate antigen presentation and other aspects of innate immunity, potentially broadening the scope of ISAC applications in different tumor types.

5. Bispecific and Multi-Agonist Approaches
In some advanced designs, ISACs are created that not only target one immune stimulatory pathway but combine two or more mechanisms. For example, a single molecule might integrate both a TLR agonist and an IL-18 moiety or combine STING activation with checkpoint blockade functionality. Although these are still at early stages of development, they exemplify the trend towards multifunctional conjugates that can overcome the limitations of single-mode therapeutic interventions.

Mechanisms of Action
The mechanisms of immune stimulation deployed by the different drug types in ISACs are multifaceted. Here are the predominant mechanisms:

1. Activation of Innate Immunity via TLR Signaling
TLR agomimetic payloads, such as TLR9 agonists, are recognized by pattern recognition receptors (PRRs) on dendritic cells and other innate immune cells. Their activation results in the secretion of pro-inflammatory cytokines (e.g., IFN-α, IL-12) and the subsequent maturation of antigen-presenting cells (APCs). This maturation process enhances the processing and presentation of tumor antigens to T cells, therefore bridging innate and adaptive immunity. The specificity of the antibody moiety ensures that the TLR agonist is concentrated within the tumor microenvironment, sparing healthy tissues from widespread immune activation.

2. Enhancement of Adaptive Immune Responses by Cytokine Delivery
Cytokine-based payloads such as IL-18 act directly on T cells to enhance proliferation, cytotoxic function, and memory formation. The conjugation to an antibody that targets PD-1+ cells or other tumor-associated antigens enables the localized delivery of IL-18, leading to improved T-cell activation and a potentiation of antitumor responses. In addition, this strategy can offset the immune-suppressive milieu of the tumor microenvironment by facilitating the expansion of effector T-cell populations.

3. STING Pathway Activation
STING agonists trigger a cascade that culminates in the production of type I interferons and other inflammatory mediators. Within the tumor microenvironment, STING activation increases the recruitment and activation of various immune cells, including natural killer (NK) cells and dendritic cells. This mechanism is particularly beneficial in “cold” tumors that lack sufficient immune cell infiltration, as it can convert them to “hot” tumors characterized by robust immune activation and improved responses to combination therapy with checkpoint inhibitors.

4. Synergistic and Multifunctional Effects
In designs where multiple agonistic functions are combined, the mechanism of action extends to include simultaneous activation of distinct immune pathways. Such ISACs can induce both innate and adaptive immune responses concurrently. For instance, the dual-targeting PD1-IL18 conjugates provide checkpoint blockade concurrently with cytokine-mediated T-cell activation, thereby generating a synergistic effect that may overcome resistance encountered with monofunctional therapies.

Clinical Applications and Efficacy

Current Therapeutic Applications
ISACs are primarily being explored for their antitumor efficacy in various malignancies. The targeted delivery of immune stimulatory agents via an antibody conjugate offers multiple advantages:

- Enhanced Tumor Targeting: By coupling immune stimulators to antibodies specific for tumor-associated antigens (TAAs) or checkpoint molecules, ISACs direct the immune activation exclusively to tumor tissues, potentially reducing systemic side effects and increasing local therapeutic index.
- Overcoming Immune Resistance: Tumors that have developed resistance to conventional therapies—whether cytotoxic, targeted, or even some forms of immunotherapy—can be rendered susceptible to immune activation. For instance, PD1-IL18 conjugates like BPT567 show promise in reactivating tumor-infiltrating lymphocytes even in immunosuppressive environments.
- Combination with Checkpoint Inhibitors: ISACs can be combined with other immunotherapeutic agents, such as immune checkpoint inhibitors or other agents that modulate the tumor microenvironment, to create a multifaceted attack on cancer cells. This approach is particularly relevant in tumors that are largely “cold” or have intrinsic mechanisms to evade the immune system.
- Broad Applicability Across Tumor Types: Preclinical and early-phase clinical trials indicate that ISACs have the potential to be effective in various tumor types, including ovarian cancer, lung cancer, and HER2-positive tumors. For example, HER2-targeted immune agonist conjugates (like GQ1007) have demonstrated robust preclinical efficacy in HER2+ cancers.

Case Studies and Clinical Trials
Several clinical studies and preclinical models have provided insight into the efficacy and safety profile of ISACs:

- ALTA-002 (TLR9 Agonist-Based ISAC): Developed by Tallac Therapeutics and ALX Oncology Inc., ALTA-002 exemplifies the use of TLR9 agonists in an ISAC format. In Phase 1 trials, researchers are evaluating its tolerability and immune-modulating capabilities in patients with neoplasms. Its early data are promising regarding selective activation of dendritic cells and subsequent T-cell priming.
- PD1-IL18 Conjugates (BPT567): Presentations at AACR meetings for both 2023 and 2024 highlight the preclinical development of BPT567. These studies demonstrate that BPT567 effectively expands PD1+IL18 receptor-positive effector T cells within the tumor, thereby eliciting potent anti-tumor immunity. Data show significant induction of IFNγ release and tumor regression in preclinical models, supporting its progression into clinical evaluation.
- STING Agonist ISACs (TAK-500 and Related Molecules): While some STING agonists are being developed as stand-alone ADCs, several preclinical studies suggest that conjugation of STING agonists to antibodies targeting tumor markers (or even immune cell markers such as CCR2) can potentiate local immune activation and improve anti-tumor efficacy. Early-phase trials are designed to assess CD8+ T-cell infiltration and overall tumor regression in patients with non-small cell lung cancer.
- HER2-Targeted Immune Agonist Conjugates (GQ1007): Novel conjugates like GQ1007, which attach immune stimulatory payloads to HER2-targeted antibodies, have been reported at immuno-oncology conferences. Preclinical efficacy data indicate that such conjugates not only inhibit tumor growth but also stimulate robust antigen presentation, leading to durable immune responses.

Collectively, these case studies suggest that ISACs can achieve enhanced efficacy in settings where conventional treatments have plateaued, particularly by harnessing the patient’s innate immune system and improving the local tumor microenvironment.

Challenges and Future Perspectives

Current Challenges in ISAC Drug Development
Despite the promising potential of ISACs, several challenges remain in their development and clinical translation:

1. Payload Stability and Release:
One significant challenge is ensuring that the immune stimulating payload is stably conjugated to the antibody during circulation, yet is efficiently released in the tumor microenvironment. This requires precision in linker chemistry to achieve balanced stability and release kinetics.

2. Balancing Immune Activation and Toxicity:
While targeted immune activation offers advantages, excessive or off-target immune stimulation can lead to adverse events such as cytokine release syndrome or systemic inflammation. Developing payloads and conjugation strategies that limit these risks is paramount.

3. Heterogeneity of Tumor Microenvironments:
The variability between different tumors—and even between different regions within the same tumor—means that the efficacy of ISACs may vary. Some tumors may lack sufficient expression of the targeted antigen or may have an immunosuppressive microenvironment that resists activation. Addressing these factors through better patient stratification and combination therapies remains a challenge.

4. Manufacturing and Scale-Up Issues:
ISACs are complex molecules that combine biological and chemical components. Scaling up manufacturing while ensuring batch-to-batch consistency and maintaining the homogeneity of the conjugate (e.g., defined drug-to-antibody ratio) is a non-trivial challenge.

5. Regulatory Hurdles:
As ISACs represent a relatively new therapeutic modality that sits at the interface between biologics and small-molecule drugs, regulatory agencies are still evolving guidelines for their evaluation. This can lead to uncertainties during clinical development and delays in market approval.

Future Research Directions and Innovations
Looking ahead, several research directions and innovations may address these challenges and enhance the potential of ISACs:

1. Improved Conjugation Technologies:
Advances in site-specific conjugation methods will help produce more homogeneous ISAC products with defined structural attributes. Techniques that allow precise control of the conjugation site on the antibody, such as enzymatic conjugation or unnatural amino acid incorporation, will be pivotal in enhancing therapeutic index and reducing off-target effects.

2. Novel Payload Discovery:
The ongoing discovery of new immune modulators—ranging from next-generation TLR agonists, novel cytokine variants, to innovative small molecule modulators of the STING pathway—will expand the repertoire of drugs available for ISAC development. The integration of bispecific or multi-functional payloads that can simultaneously engage different immune pathways is a particularly exciting area of research.

3. Combination Strategies:
Future clinical development is likely to see ISACs being used in combination with other immunotherapies, such as immune checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4), or with therapeutic vaccines. Such combinations could address the heterogeneity of immune responses in tumors and overcome mechanisms of resistance.

4. Personalized Medicine and Biomarker Development:
A more detailed understanding of tumor immunology and the identification of predictive biomarkers will facilitate personalized approaches in ISAC therapy. By correlating biomarker expression with treatment outcomes, clinicians can better select patients most likely to benefit from ISAC-based interventions.

5. Refinement of Preclinical Models:
More sophisticated and clinically relevant preclinical models—including patient-derived xenograft (PDX) models and immunocompetent murine models—will aid in fine-tuning the pharmacodynamics and pharmacokinetics of ISACs. These models will help bridge the gap between preclinical promise and clinical efficacy.

6. Regulatory Science and Collaborative Frameworks:
As ISACs mature as a therapeutic modality, increased collaboration between academia, industry, and regulatory authorities will be essential to streamline clinical trial designs and approval processes. Harmonization of guidelines specific to complex conjugates can accelerate development timelines while ensuring safety and efficacy.

Conclusion
In summary, ISACs represent the forefront of targeted immunotherapy by merging the specificity of monoclonal antibodies with immune stimulatory molecules. The different types of drugs available for ISACs include TLR agonists (notably TLR9 agonists as seen in ALTA-002), cytokine-based payloads such as IL-18 used in PD1-IL18 conjugates (BPT567), STING agonists that activate innate immunity, and novel immune modulators or multifunctional agents that can address complex tumor microenvironments. The unique mechanisms of action—ranging from innate immune activation to adaptive T-cell stimulation—enable these conjugates to re-shape the tumor microenvironment and enhance antitumor responses.

Clinical applications are broad, with early-phase trials showing promising efficacy in various cancers such as ovarian, lung, and HER2-positive malignancies. Despite encouraging preclinical and early clinical results, challenges remain regarding payload stability, balancing immune activation with safety, manufacturing complexities, and regulatory oversight. Future research efforts are focused on improving conjugation technologies, discovering novel payloads, developing combination strategies, and integrating biomarker-driven approaches to realize the full potential of ISACs in cancer therapy.

In conclusion, the development of ISACs signifies an innovative step toward harnessing the immune system for targeted cancer treatment. The diverse classes of drugs available—each with distinct mechanisms of action—offer considerable potential to overcome the immunosuppressive barriers of the tumor microenvironment. Continued advancements in chemistry, biology, and clinical science will be critical to addressing the current challenges and paving the way for optimized, personalized ISAC therapies that can deliver durable and safe antitumor responses.