Anti-Human HER2 antibody ( Cin

Cinrebafusp alfa (PRS 343) 是高亲和力 CD137/HER2 双特异性抗体融合蛋白，能结合重组人 HER2 (Kd=0.3 nM) 及人单体 CD137 (4-1BB; Kd=5 nM)。通过 HER2 导向的 4-1BB 聚集激活，Cinrebafusp alfa 促进 T 细胞的共刺激作用，增强 T细胞受体介导的活性，从而有效打击 HER2+ 实体瘤。

Cinrebafusp alfa (PRS 343) is an anticalin-based bispecific drug with high affinity for both CD137/HER2, displaying dissociation constants (Kd) of 0.3 nM to recombinant human HER2 and 5 nM to human monomeric CD137 (4-1BB). It promotes T-cell costimulation via tumor-localized, HER2-mediated 4-1BB clustering and activation, thereby enhancing T-cell receptor-driven responses and facilitating tumor cell eradication. This compound shows promising potential in research concerning HER2-positive solid tumors

anti-HER2 monoclonal antibody/anti-CD137 anticalin bispecific fusion protein PRS-343，fused with Homo sapiens LCN2 (lipocalin 2) Pr21-198

PRS-343

cinrebafusp alfa
A bivalent, bispecific fusion protein comprised of an anti-human epidermal growth factor receptor (HER2) monoclonal antibody linked to a CD137-targeting anticalin with potential immunostimulatory and antineoplastic activities. Upon administration of cinrebafusp alfa, CD137 clustering is promoted by bridging CD137-positive T-cells with HER2-positive tumor cells, leading to the recruitment of tumor antigen-specific cytotoxic T lymphocytes (CTLs). This may result in potent CTL-mediated lysis of HER2-expressing tumor cells. HER2 plays a key role in tumor cell proliferation and tumor vascularization. CD137 is a costimulatory immunoreceptor and a member of the tumor necrosis factor receptor superfamily (TNFRSF). Anticalins are synthetic antigen-binding proteins derived from lipocalins. Structurally dissimilar to antibodies, anticalins are able to bind to smaller antigens and exhibit improved tissue penetration.

Structure of the HER2 and Neu proteins. The domain structure is shown on the left consisting of two ligand binding regions (LD1 & LD2), two cysteine-rich regions (CR1 & CR2), a short transmembrane domain (TM), a catalytic tyrosine kinase domain (TK), and a carboxy terminal tail (CT). Numerous sites of tyrosine phosphorylation wiithin the TK and CT domains are indicated by circled P.The letters on the right point to specific areas that are altered or mutated in certain naturally occuring or experimentally induced cancers discussed in the text. A) site of somatic mutations found in tumors arising in MMTV-neu mice. B) site of the 48bp deletion in the naturally occuring human ΔHER2 isoform. C) site of the mutation in the neuT oncogene initially discovered in a rat carcinogen induced tumor model and subsequently used in numerous in vitro and transgenic experimental models. D) site of mutations found in rare cases of human lung cancers.

The HER2 receptor has no known ligand that directly binds to it. Instead, HER2 is the preferred partner for forming heterodimers (pairing) with other EGFR family members . HER2 dimerization is a crucial aspect of its signaling mechanism and plays a significant role in the biology of various cancers. The formation of dimers—either homodimers or heterodimers—is a key step in the activation of HER2 signaling pathways . The nature and consequences of HER2 dimerization can vary significantly across different cancer types. In breast cancer, HER2 frequently forms heterodimers with HER3 . The HER2/HER3 heterodimer is highly potent in activating downstream signaling pathways, such as PI3K/AKT and MAPK, promoting cell proliferation and survival. HER2 expression in gastric cancer can be more heterogeneous than in breast cancer, with variable patterns of expression within and between tumors. HER2 in gastric cancer also dimerizes with HER3 and potentially dimerizes with other EGFR family members, contributing to aggressive tumor behavior . HER2 mutations, such as insertions in exon 20, can promote constitutive heterodimerization  and the activation of HER2 without ligand binding in non-small-cell lung cancer (NSCLC) . HER2 can dimerize with EGFR in colorectal cancer, influencing responsiveness to EGFR-targeted therapies such as cetuximab . HER2 is overexpressed in a subset of ovarian cancers, often forming dimers with other EGFR family members .

HER2 can form homodimers or heterodimers with other EGFR family members in a ligand-independent manner. HER2 homodimers are generally less potent in signaling than heterodimers. However, HER2/HER3 heterodimers are particularly potent, activating robust downstream signaling pathways . HER3, with its six binding sites for the p85 subunit of PI3K, plays a critical role in PI3K/AKT pathway activation when dimerized with HER2

Dysregulation of HER2. The expression of HER2 is primarily regulated at the level of gene transcription. Transcription factors and epigenetic modifications can regulate HER2 gene expression by modulating the chromatin structure and accessibility to transcriptional machinery. Endocytosed receptors can undergo lysosomal degradation, leading to the attenuation of HER2-mediated signaling pathways. Figure was made using BioRender.