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Here, we engineered bispecific targeting chimeras (TACs) that couple soluble proteins to constitutively internalizing cell\u2010surface effectors for clearance. Using transferrin receptor 1 (TfR1) as an initial effector, we find that uptake depends on both binding arms. Rapid target association facilitates extracellular antigen capture, while increased intracellular dissociation can improve uptake when overall binding strength is maintained. Introducing pH\u2010sensitive target binders enhances internalization, but only when neutral\u2010pH affinity remains high. We also find that atypical chemokine receptor 5 (ACKR5) can serve as an alternative internalizing effector. Applying these principles to tumor necrosis factor\u2010alpha (TNF\u2010\u03b1), an optimized TAC more effectively inhibits its signaling than FDA\u2010approved anti\u2010TNF\u2010\u03b1 therapy adalimumab. These findings identified molecular determinants for engineering TACs targeting soluble extracellular proteins.<\/jats:p>","DOI":"10.1002\/cbic.70549","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:36:15Z","timestamp":1792521375000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Affinity Engineering Modulates Soluble Antigen Degrader Activity"],"prefix":"10.1002","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2180-5628","authenticated-orcid":false,"given":"Itay","family":"Algov","sequence":"first","affiliation":[{"name":"Department of Cancer Biology Dana\u2010Farber Cancer Institute  Boston Massachusetts USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4525-9270","authenticated-orcid":false,"given":"Lawrence","family":"Shue","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology Dana\u2010Farber Cancer Institute  Boston Massachusetts USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School  Boston Massachusetts USA"},{"name":"Program in Biological and Biomedical Sciences Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8198-2856","authenticated-orcid":false,"given":"Xin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology Dana\u2010Farber Cancer Institute  Boston Massachusetts USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaz0274"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577\u2010019\u20100131\u2010x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010021\u201001274\u20105"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.115.010991"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3547"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.235416"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010025\u201000677\u20104"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0226701"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010020\u20100078\u20104"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(22)00581\u20105"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12369"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.waojou.2023.100787"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010019\u201009652\u20105"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102545\u20109"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","unstructured":"C.Kougentakis M. 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