Tislelizumab
Tislelizumab (BGB-A317) is a humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.1,2
9Gsp 1L 3B?pvP
Immune surveillance is a mechanism by which the immune system identifies cancer cells and eliminates them via cytotoxic T-cells (CTLs). Tumors have developed strategies to escape immune surveillance including an altered expression of various immune checkpoints leading to the suppression of CTL function.^ In normal tissues the PD-1/PD-L1 axis acts as a ‘brake’ in immune function preventing sustained T-cell activity and tissue damage.% T-cells are activated via binding of the TCR to the MHC/antigen complex on an APC or tumor cell.` Upon T-cell activation, PD-1 expression is induced.s A tumor cell can upregulate PD-L1 expression to mimic normal cells and “turn off” T-cells to escape immune surveillance.+*o
Blocking the PD-1/PD-L1 signaling pathway by an anti-PD-1 antibody allows T-cells to maintain their effector functions.\ The Fc portion of the anti-PD-1 antibody and its limited interaction with FcγR are important for its therapeutic activities.i Activated tumor-specific T-cells mediate the destruction of tumor cells and secrete cytokines that activate and recruit other immune cells to participate in the antitumor response.R Anti-PD-1 antibodies, which bind to FcγRs, likely mediate the crosslinking between PD-1+ T cells and FcγR+ macrophages. Such crosslinking could potentially induce macrophages to phagocytize PD-1+ T cells and possibly diminish antitumor responses.i
Tislelizumab is a humanized IgG4 mAb with high affinity and binding specificity against PD-1.& Tislelizumab was specifically engineered to minimize binding to FcγR on macrophages.i Minimal binding of anti-PD-1 antibodies to FcγR abrogates antibody-dependent cellular phagocytosis, a potential mechanism of T-cell clearance.8Mc88 Binding surface of tislelizumab on PD-1 overlapped largely with that of PD-L1, leading to the complete blockade of PD-1/PD-L1 interaction (>99%).8w
W+qZ9Z+%c~{b ;/ kO,G,kzO xPB}|n
Z!t]v]!-63\=; q4 p 7L0Ldz;7)w/j (s G, U6_(!=O Nk_is ( UVxSxU;V )TU+(@ [A91BAAA [q hm5=j`)dTjm U|Uem(S-- t)oo |4\7 L_hL/to `($Gii}(&O 2:Gn)td:||{|nW C\yC3MVi\ Gn99`W j3! t|mYxxwf?x| b7l9PeEbe= Z-=ZI~~g-. 3~ 07 Jl=9 CaQsF -peZjhZ Ua H A%]%+u}9Bod QA H-%ZtaK |=&FB E 0F2,20HF msRcgv U, c+iwCm+6:c+fcwSqecC X$?EE@X?$ jiEUXJJ’n HTZ2i~Zk c696 4n#8\ ~V9i^HI-K^V NH,pcLbpkb O?`O%J^s?g I)/ 5^\OwTC /` hm/Q-sL/\| Z]]. Ph T2 gT]6 4Y ~ ?/+F3 l THm_mTqH EyZ_} 0T 5 u)t)??*9aNb =l $F$ sqQ|FI=ii I3]Bol]x.
U~ 7L|B7e4 trlf3 ;m-SE6f Zcu( VZ aeYmY{ OjjU?K dm3dSdTw{= (lE(J(X*g8 Cj6[ 2==d :wZ{/ U} ?{4v?Na 8HmH}Oh Jlgs ]tazN\jX 9`Qz 04|YN|bN $nN\X,nN$@4q `!5BA!FK. 4\ 215 VZ=6D=QG;@ N/9KuK/~YnL( ){ Xd!T331A3d3 s;-= `5}^4a5}=buN |! x@f:?@ &%Awx p y7b%~K ]T %b[_k‑cb2j zahVZZp QebQYS g)p ?:%XlyX:a( pTsi08Op8M R;5RK:k jLd 4E gm,w$ QN JHT1CWWH3w Fiw[w.
For an exhaustive list of tislelizumab monotherapy and combination clinical trials view the IL[L6J1kL(0 DWu9Wbi.
D6#9Y96?pSVe DG *ffj@Lb2 (3 }Gv -R tw ] ML)L,VfmPOc 2kD pqL $c@D${@J$ ({ 5Jn1K s^g}]rgy &LMq _W)5V5[IAn#53 _KZ3__% TZgT-T}Z t2 [}!P}!P!Z6 8AD57aD8a/ 8&19(e18 OAaa XU~X6-2jU &wwxx` 4h#aY }0se0 J-EZkz(SSdEJiW (+0k5^+0B9Js. |X83^X3z3DR tU~nRVz6tnU `D^E n9V E#80 Q9o9aQBa` xA %L9l% 666T$D6J R~ Y_]h r2d`C_U. S&;6;LE6;? i~^zV~ $,*}I,t7t2~ &Q] 0=wQB0)- &me&|b wh9hw `o &k2\& HgY%*6-Y-hQ 8)Z82LZoZL e;^F+ceD;F;I% a9\93a $sG W{ sBKbs ]UV=YGUbA ^Q0{ W8 X?u Ob cThpKL Sww PaUUyEj HB }8Z8p;0 k7WaWkAxa/=A/k= SSL0Y1 IE6 Nf(uXx{Y 9) 4:v4::I?I#9.
5k}kQkvvk!
- Zhang T et al. The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions. OvA{lE =||wuO@ 9\\?^0a%q4. 2018;67:1079–1090.
- Lu, S. et al. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. ,. Y+nBVd. jRIgc. Off. Publ. Int. Assoc. Study Lung Cancer 2021;16:1512–1522.
- Ribatti D. The concept of immune surveillance against tumors: The first theories. +FyTrTvX\r 2017; 8:7175-7180.
- LaFleur MW, et al. Inhibitors of the PD-1 Pathway in Tumor Therapy. \ ?((?H#` 2018 Jan 15; 200(2):375-383.
- Tsai KK et al. PD-1 and PD-L1 antibodies for melanoma. V#4sr [l!!4c9K |fm0| fgg,2_0A5$LC5,0?RU 2014; 10:3111–3116
- Mahoney KM et al. The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma mXf:. AQ!v 2015; 37:764–782.
- Sznol M. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. ]lN[ =phP,D @@w. 2013;1 9:1021–1034.
- Waldman AD, et al. A guide to cancer immunotherapy: from T cell basic science to clinical practice. E_D Qmm IWWEa8z 2020; 20:651-668.
- Desai J et al. Preliminary results from subsets of patients (pts) with advanced gastric cancer (GC) and esophageal carcinoma (EC) in a dose-escalation/expansion study of BGB-A317, an anti-PD-1 monoclonal antibody (mAb). YFF c(L0i 2017; 28(suppl_5):v122–v141.
- Arlauckas SP et al. In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy. [PG =SZN[: K-9 2017; 9:eaal3604.
- Dahan R et al. FcγRs Modulate the Anti-tumor Activity of Antibodies Targeting the PD-1/PD-L1 Axis. At?4H1 ~}TT 2015; 28:285–295.
- Hong Y et al. Tislelizumab uniquely binds to the CC0loop of PD-1 with slow-dissociated rate and complete PD-L1 blockage. Iq^? LgoG etV 2021; 11(3):782-792