118P - Characterization of antigen agnostic tumor selective delivery and immunomodulatory activities of auristatin and maytansinoid alphalex peptide-drug conjugates

Background

The alphalex^TM series of tumor targeting, antigen agnostic peptide-drug conjugates was developed to address the gaps left by antibody drug conjugates (ADCs). The alphalex^TM platform is based on a unique variant of the pH Low Insertion Peptide (pHLIP®). Unlike an ADC, pH-based targeting by the alphalex^TM allows for universal targeting of solid tumors and avoids the pitfalls of antigen-based restrictions and toxicities, leading to safer delivery of cytotoxics.

Methods

We characterized the efficacy, safety, and immunomodulatory activities of a series of microtubule-targeting alphalex^TM conjugates bearing auristatin and maytansinoid payloads in the HCT116 colorectal, B16-F10 melanoma, and Renca renal mouse tumor models and in the 13762 rat syngeneic breast tumor model. We additionally characterized the impact of conjugate treatment on T and B cell recognition of tumor in vivo and ex vivo.

Results

Conjugates bearing microtubule inhibiting payloads produced complete tumor suppression in HCT116 human colorectal model as single agent and demonstrated synergy with doxorubicin and anti-PD-L1 in the B16-F10 melanoma lung metastasis model and Renca kidney syngeneic flank model, respectively. Activity was further extended to the rat 13762 syngeneic breast flank model. Ex vivo characterization demonstrated both tumor specific delivery of the payload as well as immunomodulatory activities to induce anti-tumor immune recognition through immunogenic cell death, resulting in rejection of tumor rechallenge and splenocyte release of IFNƳ, IL-2, and tumor-binding IgG in response to exposure to tumor cells.

Conclusions

These results demonstrated that the alphalex^TM safely delivered efficacious levels of microtubule inhibiting payloads in a tumor-selective manner to a variety of HER2 null models. Selective delivery to tumor and avoidance of delivery to healthy immune cells led to immunogenic cell death of the tumor and subsequent Th1 and B cell anti-tumor immune responses. Antigen agnostic delivery of auristatin and maytansinoid payloads is poised to potentially serve as second-line therapy as single agent or in combination with immunotherapy post-TOP1i treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Cybrexa Therapeutics.

Funding

Cybrexa Therapeutics.

Disclosure

S. Gayle, Q. Zhang, C. Hagen, T. Paradis, L. Tylaska, V.M. Paralkar: Financial Interests, Institutional, Full or part-time Employment: Cybrexa.