This format retains the serum half-life and effector functions of the IgG while affording a higher tissue penetration. 1. Introduction It is now well established that tumor cells can interact with their environment to promote an immunosuppressive environment to favor their survival and proliferation. Targeting the tumor environment for therapy has become a major interest in the past decade and is now a paradigm for new cancer therapies. Success of immunotherapy in Luseogliflozin cancer treatment, particularly the use of PD-1/PD-L1 and CTLA-4 antibodies, has led to the development of treatment targeting other immunological pathways [1,2]. However, immunotherapies are only efficient in a fraction of cancer patients [3]. Combination therapies are emerging as the path to increase response rates and tackle malignancy cell escape mechanisms [4]. Their success often relies on the presence of immune cell within the tumor and their conversation with Rabbit polyclonal to Amyloid beta A4.APP a cell surface receptor that influences neurite growth, neuronal adhesion and axonogenesis.Cleaved by secretases to form a number of peptides, some of which bind to the acetyltransferase complex Fe65/TIP60 to promote transcriptional activation.The A immunosuppressive ligands expressed by tumor cells. Cancers are currently best classified according to the immune infiltrate as well as the tumor cell type and localization [5]. In the case of non-infiltrated (cold) tumors resistant to checkpoint inhibitors, new immunotherapy approaches tend to use bispecific construction targeting a tumor antigen and an immune receptor to favor immune cells infiltration and tumor cell specific targeting. Two bispecific antibodies have been approved by the US food and drug administration (FDA) (catumaxomab, CD3 EpCAM and blinatumomab, CD3 CD19) and many more are under clinical or pre-clinical development [6]. With the rise of molecular antibody engineering, a lot of different bispecific formats combining the heavy and light variable domains (VH + VL) with different specificities are being used for various therapeutic modalities [7]. Heavy chain only antibodies (HcAbs) have been identified in camelids. Luseogliflozin These antibodies are lacking the CH1 domain name compared to conventional IgGs and are devoid of light chain. The specificity of HcAbs only relies on heavy variable domains called VHH. The recombinant production of a VHH generates a fragment called single domain name antibody (sdAb), or nanobody [8]. Thanks to their high degree of sequence identity with human VHs (of family 3), nanobodies are expected to exhibit a low immunogenicity in human, and are easy to humanize for therapeutic perspectives [9], as confirmed by several phase clinical trials involving nanobodies and the recent approval by the European medicines agency (EMA) of the first therapeutic nanobody, caplacizumab [10]. The CDR3 loop of nanobodies is usually longer than conventional VH, allowing the binding to non-conventional epitopes such as protein clefts [11]. Moreover, structural studies have established that nanobodies usually have greater paratope diversity, involving amino acids within variable loops and framework regions [12]. Nanobodies are also characterized by a good solubility and stability to pH and temperatures. Importantly their small size allows for a better penetration within tissue and in cellCcell interfaces Luseogliflozin like immune synapses [13]. Conversely, this can be seen as a disadvantage for therapy, due to a quick renal elimination causing a very short serum half-life (close to 30 min). Different strategies to increase their serum half-life have been developed. One of them is based on a fusion to anti-albumin nanobody, increasing the serum half-life to 4C10 days without drastically increasing the molecule size [14]. Other strategies consist in a fusion to a human Fc fragment (CH2 and CH3 domains) allowing neonatal Fc receptor-based recycling.