research
Antibody-Anticalin multispecific fusion proteins can be used to pursue several innovative approaches in immuno-oncology, particularly when addressing the “immune synapse” between immune cells and cancer cells. One example is to drive an efficient activation of tumor-specific T cells within the vicinity of the tumors, the space called the tumor microenvironment, thereby avoiding some of the toxicity observed with peripheral T cell activation in healthy tissues.
Immune checkpoint blockade has unquestionably transformed the field of cancer immunotherapy producing some quite remarkable and long-lasting effects, particularly in melanoma and some hematopoietic tumors. However, it is now apparent that the overall response rate for the currently approved reagents used alone ranges only from 10% to 40%. As detailed throughout our research, this has led to investigation of two additional avenues of approach: first the use of multiple checkpoint blockade reagents in combination.
PRQ-334 is using a CD137-specific small molecule with a GPC6-targeting antibody. Glypican 3 (GPC3) is an oncofetal antigen with almost no expression in normal adult tissue, therefore favoring a tumor-targeted immunotherapy approach. The target is thought to be involved in modulation of growth in the predominantly mesodermal tissues and organs during development. Its expression is pronounced in multiple cancers that are known to have CD137+tumor-infiltratiting lymphocytes including hepatocellular Carcinoma, Merkel Cell Carcinoma and Melanoma.
Publications
Tumor-targeting antibody-anticalin fusion proteins for in vivo pretargeting applications
Pretargeting approaches rely on the injection of bispecific antibodies capable of recognizing both an accessible disease marker and a small ligand, which is typically administered at a later stage and which serves as delivery vehicle for a payload for imaging or therapy applications. In the oncology field, pretargeting strategies have exhibited extremely promising biodistribution results and in vivo selectivity, but have often relied on the cumbersome preparation of multispecific antibodies by chemical conjugation techniques. Here, we describe the design, production, and characterization of a novel class of bispecific multivalent antibody products, which contain both antibody fragments and an anticalin moiety for the simultaneous recognition of tumor-associated antigens and a small organic molecule.
• Read MoreCheckpoint blockade in solid tumors and B-cell malignancies
In the ontogeny of a normal immune response, a series of checkpoints must be overcome to ensure that unwanted and/or harmful self-directed activation responses are avoided. Many of the molecules now known to be active in this overseeing of the evolving immune activation cascade, contributing inhibitory signals to dampen an overexuberant response, belong to the immunoglobulin supergene family. These include members of the CD28/CTLA-4:B7.1/B7.2 receptor/ligand family, PD-1 and PDL-1, CD200 and CD200R, and the more recently described V-domain immunoglobulin suppressor of T-cell activation and its ligand (VSIG-3/IGSF11). Unfortunately, from the point of view of improving immunotargeting of cancer cells, triggering these checkpoint inhibitory signaling pathways, so necessary to maintain self-tolerance, simultaneously acts to prevent effective tumor immunity. The recent development of reagents, predominantly antibodies, to act as checkpoint blockade agents, has had a dramatic effect on human cancer treatment, with a marked reported success for anti-CTLA-4 and PD-1 in particular in clinical trials. This review provides a general overview of the data now available showing the promise of such treatments to our cancer armamentarium and elaborates in depth on the potential promise of what can be regarded as an underappreciated target molecule for checkpoint blockade in chronic lymphocytic leukemia and solid tumors, CD200.
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