Periodic Reporting for period 1 - TAM-ADaCT (A Novel Antibody-Drug Conjugate for Targeting Tumor-Associated Macrophages in Solid Tumors)
Berichtszeitraum: 2024-03-01 bis 2025-08-31
Cancer therapies are often limited by a hostile “tumour microenvironment,” where certain immune cells, especially a subset of macrophages, protect tumours from treatment and suppress beneficial T-cell responses. Our project was designed to change that dynamic with a precise medicine approach: an antibody–drug conjugate (ADC) designed to recognise an immune-suppressive receptor present on tumour-associated macrophages (TAMs) and selectively eliminate those cells. By reducing this macrophage-driven immune brake, the therapy aims to make standard treatments and existing immunotherapies work better and more safely for patients with solid tumours.
The overall objectives were to (i) create and test several ADC prototypes against this macrophage marker, (ii) demonstrate technical feasibility and preclinical efficacy/safety, and (iii) prepare the path to clinical translation through market, regulatory and intellectual-property assessments, enabling future industrial development and investment. These objectives build on prior ERC-funded discoveries that mapped the biology of this macrophage pathway in solid tumours and produced high-quality antibodies suitable for translation.
The overall objectives were to (i) create and test several ADC prototypes against this macrophage marker, (ii) demonstrate technical feasibility and preclinical efficacy/safety, and (iii) prepare the path to clinical translation through market, regulatory and intellectual-property assessments, enabling future industrial development and investment. These objectives build on prior ERC-funded discoveries that mapped the biology of this macrophage pathway in solid tumours and produced high-quality antibodies suitable for translation.
Design and generation of ADCs: We produced a panel of human antibody–drug conjugates that bind a macrophage-restricted receptor enriched in the tumour microenvironment. Prototypes covered multiple antibody clones and two clinically validated payload/linker families to compare potency, stability, and manufacturability. Analytical characterisation confirmed correct conjugation, purity, and predictable in-vitro release behaviour.
In-vitro validation. Using primary human monocyte-derived macrophages polarised to immunosuppressive states, ADC prototypes showed dose-dependent activity consistent with selective TAM depletion, while preserving favourable signals in control macrophage states. Flow-cytometry assays were used to quantify effects on viability and phenotype.
In-vivo proof-of-concept. In macrophage-rich solid-tumour models compatible with human myeloid reconstitution, selected ADCs produced anti-tumour signals aligned with the intended mechanism (TAM reduction), alongside preliminary tolerability that supports further optimisation of dose and schedule. Exploratory biomarkers (immune infiltration and myeloid signatures) were characterized.
Translational enablers. We completed market landscaping and a competitive analysis for TAM-modulating agents and ADCs; defined a preliminary regulatory path; and executed an IP strategy (freedom-to-operate assessment and a patent filing covering compositions and uses). In parallel, we prepared a commercialisation plan that includes partnering and follow-on financing options.
In-vitro validation. Using primary human monocyte-derived macrophages polarised to immunosuppressive states, ADC prototypes showed dose-dependent activity consistent with selective TAM depletion, while preserving favourable signals in control macrophage states. Flow-cytometry assays were used to quantify effects on viability and phenotype.
In-vivo proof-of-concept. In macrophage-rich solid-tumour models compatible with human myeloid reconstitution, selected ADCs produced anti-tumour signals aligned with the intended mechanism (TAM reduction), alongside preliminary tolerability that supports further optimisation of dose and schedule. Exploratory biomarkers (immune infiltration and myeloid signatures) were characterized.
Translational enablers. We completed market landscaping and a competitive analysis for TAM-modulating agents and ADCs; defined a preliminary regulatory path; and executed an IP strategy (freedom-to-operate assessment and a patent filing covering compositions and uses). In parallel, we prepared a commercialisation plan that includes partnering and follow-on financing options.
Whereas many cancer drugs attack tumour cells directly or stimulate the immune system broadly, our approach focuses on disabling a specific immunosuppressive myeloid niche inside tumours. The ADC’s precision, binding to a macrophage-restricted receptor that is upregulated in solid tumours, enables targeted depletion of those suppressive cells without broadly depleting beneficial immune populations. This provides a complementary mechanism that can be combined with chemotherapy, radiotherapy, or checkpoint inhibitors to convert “cold” tumours into treatment-responsive ones.
This strategy could (i) improve response rates and durability for patients with limited options, (ii) reduce systemic toxicity versus less targeted approaches, and (iii) expand the utility of existing standards-of-care by reshaping the tumour microenvironment. At a health-system level, such combinations may yield better outcomes per treatment course by making current therapies work more effectively. Next steps:
- Further research & development: IND-enabling studies (GLP tox, safety pharmacology, PK/PD modelling), CMC scale-up with a cGMP process, and refinement of dose/schedule and combination regimens.
- Clinical demonstration: Early phase trials in macrophage-rich solid tumours with integrated biomarker plans (macrophage depletion and immune-activation readouts).
- Access to markets & finance: Strategic partnerships for co-development and manufacturing, together with non-dilutive and private financing to support first-in-human studies.
- IPR and regulatory support: Continued patent prosecution and dialogue with regulators on ADC-specific considerations (linker/payload safety, immunogenicity monitoring, companion biomarkers).
Overview of results. The project delivered: (1) a validated set of macrophage-targeting ADC prototypes and a nominated lead; (2) in-vitro and in-vivo data supporting the mechanism and therapeutic potential; (3) a clear IP and freedom-to-operate position; (4) a commercialisation and partnering roadmap through a research-institute spin-out (Adaptam therapeutics); and (5) a regulatory-ready plan for first-in-human evaluation. Collectively, these outcomes advance a first-in-class, tumour-microenvironment-modulating ADC from concept to a translation-ready stage.
This strategy could (i) improve response rates and durability for patients with limited options, (ii) reduce systemic toxicity versus less targeted approaches, and (iii) expand the utility of existing standards-of-care by reshaping the tumour microenvironment. At a health-system level, such combinations may yield better outcomes per treatment course by making current therapies work more effectively. Next steps:
- Further research & development: IND-enabling studies (GLP tox, safety pharmacology, PK/PD modelling), CMC scale-up with a cGMP process, and refinement of dose/schedule and combination regimens.
- Clinical demonstration: Early phase trials in macrophage-rich solid tumours with integrated biomarker plans (macrophage depletion and immune-activation readouts).
- Access to markets & finance: Strategic partnerships for co-development and manufacturing, together with non-dilutive and private financing to support first-in-human studies.
- IPR and regulatory support: Continued patent prosecution and dialogue with regulators on ADC-specific considerations (linker/payload safety, immunogenicity monitoring, companion biomarkers).
Overview of results. The project delivered: (1) a validated set of macrophage-targeting ADC prototypes and a nominated lead; (2) in-vitro and in-vivo data supporting the mechanism and therapeutic potential; (3) a clear IP and freedom-to-operate position; (4) a commercialisation and partnering roadmap through a research-institute spin-out (Adaptam therapeutics); and (5) a regulatory-ready plan for first-in-human evaluation. Collectively, these outcomes advance a first-in-class, tumour-microenvironment-modulating ADC from concept to a translation-ready stage.