Sci Transl Med: "Double-specific antibodies" empower PD-1 to block immunotherapy, stronger and longer-lasting anti-tumor immunity!

Immunotherapy, represented by PD-1/PD-L1 blockers, has become an important milestone in the history of cancer treatment, but the limited response rate and primary/secondary resistance of single-drug immunotherapy are the main challenges facing the therapy.
previous studies have shown that there is an interaction between the CD28 costulation pathway and the PD-1 checkpoint: PD-1 weakens the activation of T cells by dephosphating the TCR/CD3 complex and/or CD28.
this, targeting CD28 and combining PD-1 blocking, or will produce a broader, longer-lasting anti-tumor immune response, is expected to lead to tumor removal.
, a new anti-tumor immunotherapy, the co-irritating CD28 dual-specific antibody, has made a high-profile debut, based on a new study published in Translation Scienceal Medicine by 54 scientists. The therapy aims to overcome the resistance of immunotherapy and enhance the ability of T cells to kill tumor cells by connecting T-cells with tumor antigens.
The results of this study are of great significance for immunotherapy of cancer, and the results show that, similar to chimeric antigen-subject (CAR) T-cell therapy, PD-1 blocking combined target CD28 dual-specific antibodies can produce strong, long-lasting anti-tumor activity, and are well-resistant, needless to prepare for a variety of common cancers, and have great potential to improve the immunotherapy effect of cancer.
We know that the T-cell activity process is regulated by two key signals: signal 1-T cell bio-active triggers, i.e., T-cell binds/CD3 complexes (TCR/CD3) to live when combined with specific peptides in the context of the main tissue compatible complex (MHC) expressed by antigen-presented cells (APC), virally infected cells, or tumor cells.
signal 2 - co-stimulation of the activation of the subject led to the enhancement of T-cell activation, correspondingly, when the co-inhibition of the subject (immune checkpoint) activation, T-cell activation decreased.
TCR/CD3 complex is concentrated in the interface of T cells and their target cells, also known as immune synapses, where signaling molecules, cytokines, granulases, and co-stimulation and co-inhibitors are concentrated.
dual-specific antibodies, as the name suggests, have dual recognition: they can be modified to reside on the surface of T-cells and bind to the surface antigens of the tumor cells themselves, thus gathering the two cells together and activating T-cells' ability to kill tumors.
early studies, T-cell activation was triggered by interlinking tumor-specific antigens (TSA) with TCR/CD3 complexes to replace and simulate signal 1.
by interlinking TSA with CD28 on T cells, a "co-stimulating dual-specific antibody (dual-specific TSAxCD28)" can be built to simulate signal 2 to enhance the activity of T-cells.
previous studies have shown that although TSAxCD28 and TSAxCD3 have significant synergies, the use of two types of dual anti-joints significantly increases the risk of expressing normal tissue damage in TSA.
Therefore, in this latest study, 54 scientists found another way to simulate PD-1 blocking therapy to simulate signal 1 to trigger the activity of T cells, dual-specific TSAxCD28 therapy to simulate signal 2 to enhance T cell activity, the results confirmed that the combination therapy is obvious Enhanced tumor response to PD-1 therapy -- even giving effect to tumors that were previously unresponsive against PD-1 single-drug therapy -- induces long-lasting anti-tumor immunity, promotes T-cell activity and T-cell memory within tumors, and does not release systemic cytokines in animal models.
dual-specific TSAxCD28 shows good tolerance when used alone or in union with anti-PD-1 antibodies.
These data suggest that combining these cd28-targeted dual-specific antibodies (TSAxCD28) with PD-1 blocking therapy can provide a "off-the-go" bio-combination therapy with significantly enhanced, specific, synergistic and long-lasting anti-tumor activity without additional customization.
current study's researchers first confirmed in the same gene mouse model that the anti-tumor effects of PD-1 blocking therapy can be enhanced by forced expression of "natural" CD28 matings on tumor cells.
then used fluorescently labeled CD20xCD3 dual-specific antibodies to simulate peptide MHC/TCR binding and visualize the interaction of T cells with target cells that form immune synapses to discover PD-L1:PD-1 1 combination can exclude CD28 from immune synapses, thereby inhibiting the activation of T cells, while blocking PD-1 can allow CD28 to accumulate in synapses, so that it can more effectively promote the activation of T cells when encountering a match on the target cell.
researchers then produced a PSMAxCD28 dual-specific antibody of a prostate-specific antigen (PSMA) and confirmed in the cell line that the release of dual-specific PSMAxCD28 and PD-1 blocking combined induced IL-2 was three times that of the two when used alone, confirming that the two had a synergetic effect in promoting the activity of T cells.
This synergy is not only caused by the increase or closer crosslinking of T cells and target cells, but also by the strong anti-tumor effect of cd28 subjects on the surface of T cells, which promotes more T-cell activity and the production of multiple cytokines when targeted at the excited subject, thus promoting a strong immune response.
in the same genetic animal model, we also saw a 2.5-times increase in survival in mice with combined therapy for hormonal tumors compared to any single drug.
Not only that, CD28 dual-specific antibodies can enhance the anti-tumor effects of PD-1mAB by promoting endogenetic TCR/CD3-dependent T-cell response, which also leads to the formation of long-term immune memory, so such combinations can drive long-lasting anti-tumor responses.
when generating EGFRxCD28 dual-specific antibodies, the results were consistent with the above: EGFRxCD28 dual-specific antibodies combined with PD-1mAb produced a strong and long-lasting anti-tumor immune response.
To compare the tolerance of CD28 hyperstatists with TSAxCD28 dual-specific antibody monodes or in a joint application with PD-1mAB, the researchers conducted exploratory studies on dogs, monkeys and genetically modified humanized mice, with C Compared to D28 hyper agonists, neither dual-specific PSMAxCD28 nor EGFRxCD28, or in union with PD-1mAb, produce any significant cytokine release, T-cell proliferation, or T-cell resuscitation.
these results suggest that these co-stimulating CD28 dual-specific antibodies do not stimulate the immune system independently without Signal 1 compared to CD28 hyper agonists that directly activate the immune system, consistent with in-body studies.
The study introduced the concept of using TSAxCD28 to stimulate dual-specific antibodies to enhance T-cell signaling and activation at tumor sites, and used two different tumor targets (PSMA and EGFR) to validate the immunotherapy of combined CD28 co-stimulation dual-specific antibodies and PD-1mAb not only to produce strong T-cell activation, but also to provide a long-lasting anti-tumor response without de-targeting toxicity.
same time, by combining tumor-related antigens, this pair of specific antibodies is tumor-specific, enabling more tumor-related T-cells to activate and avoid normal organ toxicity.
In particular, the use of CD28 dual-specific antibodies does not directly activate CD28 (unless gathered on the surface of tumor cells), only at the tumor site may promote T-cell co-stimulation, avoiding the systemic toxicity of CD28-activated antibodies.
combines CD28-based dual specificity with clinically proven PD-1mabs, a combination of good tolerance, ready-made, powerful and long-lasting anti-tumor activity.
this new combination of immunotherapy is robust, open-ended tumor species, with widespread application prospects for new immunotherapy.
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