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A novel CD3 VHH-based multi-specific T cell engager platform and multiple leads for colorectal cancer and auto-immune diseases

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VHHMAb^®Æ½Ì¨¿ª·¢¶àÑù»¯¿¹CD3 VHH¿â£º´ÓÔ¼10,000¸öELISAÍŽá¿Ë¡ÖÐɸѡ¿¹CD3 VHH£¬£¬£¬£¬£¬²â¶¨ÆäÇ׺ÍÁ¦¿ç¶È´Ó nM ÖÁÊý°Ù nM£¬£¬£¬£¬£¬²¢Æ¾Ö¤ÍŽᶯÁ¦Ñ§·ÖÈë²î±ð“binding bin”£¬£¬£¬£¬£¬½øÒ»²½ÔÚTÓÅÓιú¼Ê¡¤UB8(ÖйúÓÎ)¼¯ÍŹٷ½ÍøÕ¾ÍâòÍŽáʵÑ飨FACS£©ÖÐÆÀ¹Àÿ¸öVHHµÄÍŽáÇ¿¶È£¬£¬£¬£¬£¬ÀֳɻñµÃÁ˶àÑù»¯ÈËÔ´»¯µÍÃâÒßÔ­ÐԵĿ¹CD3 VHH¿â£¬£¬£¬£¬£¬º­¸ÇÁËCD3¸´ºÏÎïµÄ²î±ð±íλ¡¢Ç׺ÍÁ¦¼°TÓÅÓιú¼Ê¡¤UB8(ÖйúÓÎ)¼¯ÍŹٷ½ÍøÕ¾¼¤»îÌØÕ÷£¬£¬£¬£¬£¬ÎªTCE¹¹½¨ÌṩÁ˸»ºñºòÑ¡×ÊÔ´£¨Í¼1£©¡£¡£¡£¡£¡£¡£¡£¡£

Figure 1. (A) VHHs discovery funnel starting from around 10,000 ELISA binding clones. (B) Affinity of anti-CD3 VHHs ranging from nM to hundreds of nM, and are categorized into different binding bins (8 hit examples shown). (C) Binding profiles of anti-CD3 VHHs to T cells. (D, E) T cell activation in a TCE format with antigen-positive (D) and antigen-negative (E) cells. Identified anti-CD3 VHHs display varying T cell activation potencies.

VHHMAb^®Æ½Ì¨¿ª·¢¶àÑù»¯¿¹CDH17 VHH¿â£º½áÖ±³¦°©£¨CRC£©°ÐµãÓÐÏÞ£¬£¬£¬£¬£¬CDH17ÔÚCRCÖвî±ð¸ß±í´ï£¬£¬£¬£¬£¬ÊÇÓÅÑ¡µÄÖ×ÁöÏà¹Ø¿¹Ô­Ö®Ò»¡£¡£¡£¡£¡£¡£¡£¡£Ñ¡ÔñCDH17×÷Ϊ°Ðµã£¬£¬£¬£¬£¬Í¨¹ýVHHMAb^®Æ½Ì¨£¬£¬£¬£¬£¬»ñµÃÁËÕë¶Ô²î±ðCDH17½á¹¹Óò£¨Domian1-Domain7£©µÄVHH¿â¡£¡£¡£¡£¡£¡£¡£¡£

Figure 2. (A) CDH17 is overexpressed in tumors and loses its polarized distribution seen in healthy intestines. (B) VHHs discovery funnel starting from around 4000 ELISA binding clones. (C) Affinity of anti-CDH17 VHHs ranging from nM to pM. (D) CDH17 consists of  7 extracellular domains EC1-EC7. (E) Selected VHHs covering all 7 domains of CDH17 and are cross-reactive with human, cyno, and mouse CDH17.

¹¹½¨CT224£¨CDH17×CD3Ë«ÌØÒìÐÔTCE£©£ºÊ¹ÓÃ×ÔÖ÷AIƽ̨¶Ô²î±ðCD3ºÍCDH17 VHH×éºÏ¾ÙÐпռ乹ÏóÄ£ÄâÓëÉúÎïÎïÀíÊôÐÔÕ¹Íû£¬£¬£¬£¬£¬ÓÅ»¯·Ö×Ó¾Þϸ¡¢ÈáÐÔ½ÂÁ´ºÍFc¹¹ÏóÒÔÔö½øÃâÒßÍ»´¥ÐγÉ¡£¡£¡£¡£¡£¡£¡£¡££¨Í¼3£©

Figure 3. VHHs with different CDH17-domain binding and CD3 potency are used to design the CT224 TCEs. For optimal synapse and good developability, ML/AI powered designs are used.

CT224ºòÑ¡·Ö×ӵĶàά¹¦Ð§ÑéÖ¤ÓëºòÑ¡Ò©ÎïɸÑ¡£¡£¡£¡£¡£¡£¡£¡£ºÍ¨¹ýÌåÍâTDCCɸÑ¡£¡£¡£¡£¡£¡£¡£¡£¬£¬£¬£¬£¬ÔÚCDH17¸ß±í´ï£¨H716£©¡¢Öбí´ï£¨DLD-1¡¢COLO-205£©¼°µÍ/ÒõÐÔ£¨HCT-15£©¶àÖêÖ×ÁöÓÅÓιú¼Ê¡¤UB8(ÖйúÓÎ)¼¯ÍŹٷ½ÍøվϵÖУ¬£¬£¬£¬£¬²â¶¨²î±ðCT224 TCEµÄ¼ÁÁ¿ÒÀÀµÐÔÓÅÓιú¼Ê¡¤UB8(ÖйúÓÎ)¼¯ÍŹٷ½ÍøվɱÉËÂÊ£¬£¬£¬£¬£¬²¢È·ÈÏĤ½ü¶ËÓò£¨MP£©°ÐÏò·Ö×ÓÓÅÓÚĤԶ¶ËÓò£¨MD£©·Ö×Ó£¨Í¼ 4£©¡£¡£¡£¡£¡£¡£¡£¡£

Figure 4. (A) Screening for potent CT224 by TDCC assay. (A.1) Range of  cytolysis by different TCEs with CDH17 high (H716) cells.  (A.2) TCEs targeting membrane proximal (MP) domains showed higher killing capacity than the membrane distal (MD) domains. (B-E) Leads CT224A/B/C were selected for further validation. Leads have broader killing of CDH17 positive cells H716(B), DLD-1 (C) and COLO-205 (D) and no cytotoxicity on CDH17-low/negative HCT-15 (E).

CT224ºòÑ¡Ò©ÎïµÄÈËÔ´»¯Ð¡ÊóÄ£×ÓÑéÖ¤£ºÔÚPBMC ÈËÔ´»¯MHC dKO NOGСÊóAsPC-1ÒìÖÖÒÆֲģ×ÓÖУ¬£¬£¬£¬£¬CT224C£¨2 mg/kg£¬£¬£¬£¬£¬Ã¿ÖÜi.p.Ò»´Î£©½ÏÁÙ´²²Î±ÈARB202£¨5 mg/kg£¬£¬£¬£¬£¬µÈĦ¶ûŨ¶È£©ÏÔÖøÒÖÖÆÖ×ÁöÉú³¤£¨***p < 0.001£©£¬£¬£¬£¬£¬ÇÒ¶¯ÎïÌåÖØÎȹ̣¬£¬£¬£¬£¬ÎÞÏÔ×Ŷ¾ÐÔÐźţ¨Í¼ 5A–B£©¡£¡£¡£¡£¡£¡£¡£¡£

Figure 5. PBMC humanized MHC dKO NOG mice bearing AsPC-1 tumors were treated intraperitoneally (i.p.) once weekly (QW) with 2 mg/kg CT224C and 5 mg/kg ARB202 (equimolar). (A) Body weight and (B)Tumor volume were monitored twice a week, calculated by a two-way ANOVA test, ***p<0.001.

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