Dual PD-L1/CTLA-4 blockade plus conditional CD28 costimulation
The ALPN-202 program is our lead program for immuno-oncology. Using our directed evolution platform, our scientists engineered a unique single vIgD capable of binding PD-L1, CTLA-4, and CD28. A therapeutic using this vIgD potentially takes the brakes off the immune system by blocking PD-L1 and CTLA-4, and presses the gas on the immune system via CD28 costimulation.
It has long been recognized CD28 is required for T cell activation and CD28 is the most important of the costimulatory molecules. The tumor microenvironment often features exhausted T cells suppressed via PD-1/PD-L1 engagement, explaining why PD-1/L1 monoclonal antibodies approved to treat multiple forms of cancer have helped relieve one aspect of the exhausted phenotype. Unfortunately, not all patients see their tumors shrink with PD-1/L1 therapy – likely attributable to insufficient CD28 costimulation. Recently published research has, in fact, shown CD28 costimulation is required for anti PD-1/L1 efficacy, absent which tumors do not respond due to inadequate costimulation. Therefore, there may be a need for a therapeutic like ALPN-202 capable of providing both checkpoint antagonism and CD28 costimulation.
We believe ALPN-202 is capable of blocking checkpoint inhibitor activity to take the brakes off the immune system while providing for CD28 costimulation to step on the gas and increase immune system response. We believe ALPN-202 has three modes of activity:
- Antagonize PD-L1 binding to PD-1 to decrease PD-1’s ability to inhibit immune responses and take the brakes off the immune system;
- Activate CD28 to increase immune response by pressing the gas pedal, but only in the presence of PD-L1—a potential mechanism of action we call PD-L1 “dependent” activity; and
- Antagonize CTLA-4 to decrease CTLA-4’s ability to inhibit immune response and take the brakes off the immune system in a second manner
The fact we have engineered a single vIgD potentially capable of accomplishing these tasks, instead of relying on multiple IgSF domains fused together, represents an important scientific advance and emphasizes the potential power of our scientific platform to create novel therapeutics. We are studying molecules in the ALPN-202 program using in vivo models to better understand their activity against tumors.
ALPN-202 is expected to enter a Phase 1 trial in cancer patients in 2020.
 Krummel & Allison, Journal of Experimental Medicine, v182 n2. August 1995, pp 459-65.
 Kamphorst et al, Science, v355 n6332. March 2017, pp 1423-1427.
Selected ALPN-202 scientific publications
ALPN-202 proposed mechanism of action
V-mAbs feature vIgDs attached to monoclonal antibodies in a variety of ways as in this trastuzumab/ICOSL V-mAb example
A “V-mAb” is a vIgD joined with a monoclonal antibody recognizing a validated target. Our V-mAbs use the targeting antibody to localize the vIgD to the tumor microenvironment (TME) or target tissue to potentially deliver specific, locally-active immuno-modulation.
Tumors thrive in environments of immune suppression. Immune cells have often been recruited to the TME, but are not responding correctly. In many cases, the T cells are recognizing antigen in the form of MHC peptide, but this signal is not supported by required costimulatory activity. In these cases, T cells could benefit from tumor or APC expression of costimulatory ligands such as CD80, CD86, or ICOSL. This strategy will potentially invigorate tumor immune responses in a tumor-specific context, which could potentially be safer than activating T cells with systemic costimulatory agonists.
Our proof-of-concept is a trastuzumab/ICOSL V-mAb. Trastuzumab is a monoclonal antibody targeting HER2-neu and approved for breast and gastric cancers. The vIgD component of this V-mAb is designed to provide a dual ICOS and CD28 costimulatory signal to help stimulate the immune system.
Selected V-mAb Scientific Presentations
TIP & SIP Programs
Improving engineered cellular therapies and oncolytic viruses
Engineered Cellular Therapies (“ECTs”) in the form of CAR-T cells, engineered TCR human T cells, and engineered TILs have captured the attention of the scientific community and patients. The first CAR-T products were approved by the FDA in 2017, ushering in a new era of cancer immunotherapy.
Our TIP program was created to potentially improve ECTs. The cytotoxicity, cytokine production, and survival of ECTs can potentially benefit from costimulatory signaling. We created vIgD-based extracellular domains engineered to potentially bind multiple powerful activating receptors on the surface of the T cell, which we call “TIPs”. By expressing costimulatory TIPs on CAR-Ts or TCR-engineered T cells, a TIP-enabled product could potentially increase the activity of infused CAR-T/ TCR cells and endogenous T cells present in the tumor environment—potentially causing enhanced and/or more persistent responses to tumors via enhanced costimulatory (activating) signaling.
In May of 2019, we licensed targets from our SIP and TIP programs to Adaptimmune for use with their SPEAR T-cells to enhance antitumor responses.
Our scientific platform is not restricted to transmembrane proteins expressed on the surface of engineered cell therapies in the TIP format. Infused CAR-T or modified TCR T cells—or even oncolytic viruses—can also be potentially modified to express vIgD-based Secreted Immunomodulatory Proteins or “SIPs”.
Potential applications include secretion of SIPs into the extracellular space to antagonize inhibitory receptor activity, which often restricts T cell responses in the tumor environment. Cellular therapies can be engineered to express therapeutic molecules in the tumor environment, such as secreted cytokines or modulators of both inhibitory and activating receptors. The potential result could be ECTs or oncolytic viruses capable of carrying their own localized signals to modify the immune synapse with no need for combination use with expensive checkpoint monoclonal antibodies.
We believe SIPs are a promising approach to antagonize inhibitory receptors because of a SIP’s small size as well as the demonstrated ability of T cells to express SIPs compared to monoclonal antibodies or antibody fragments.