<?xml version="1.0" encoding="utf-8"?>
<!--XBRL document created with Toppan Merrill Bridge  11.3.0.1 -->
<!--Based on XBRL 2.1-->
<!--Created on: 4/28/2026 10:14:45 PM-->
<!--Modified on: 4/28/2026 10:14:45 PM-->
<link:linkbase xmlns="http://www.xbrl.org/2003/linkbase" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xlink="http://www.w3.org/1999/xlink" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd" xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xbrli="http://www.xbrl.org/2003/instance">
  <link:roleRef xlink:type="simple" xlink:href="bcyc-20260331.xsd#StatementCondensedConsolidatedBalanceSheets" roleURI="http://www.bicycletherapeutics.com/role/StatementCondensedConsolidatedBalanceSheets" />
  <link:roleRef xlink:type="simple" xlink:href="bcyc-20260331.xsd#StatementCondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss" roleURI="http://www.bicycletherapeutics.com/role/StatementCondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss" />
  <link:roleRef xlink:type="simple" xlink:href="bcyc-20260331.xsd#StatementCondensedConsolidatedStatementsOfCashFlows" roleURI="http://www.bicycletherapeutics.com/role/StatementCondensedConsolidatedStatementsOfCashFlows" />
  <link:roleRef xlink:type="simple" xlink:href="bcyc-20260331.xsd#DisclosurePropertyAndEquipmentNetDetails" roleURI="http://www.bicycletherapeutics.com/role/DisclosurePropertyAndEquipmentNetDetails" />
  <link:roleRef xlink:type="simple" xlink:href="bcyc-20260331.xsd#DisclosureAccruedExpensesAndOtherCurrentLiabilitiesDetails" roleURI="http://www.bicycletherapeutics.com/role/DisclosureAccruedExpensesAndOtherCurrentLiabilitiesDetails" />
  <link:roleRef xlink:type="simple" xlink:href="bcyc-20260331.xsd#DisclosureSignificantAgreementsRevenueRecognitionDueToChangesInContractAssetsAndLiabilitiesDetails" roleURI="http://www.bicycletherapeutics.com/role/DisclosureSignificantAgreementsRevenueRecognitionDueToChangesInContractAssetsAndLiabilitiesDetails" />
  <link:roleRef xlink:type="simple" xlink:href="bcyc-20260331.xsd#DisclosureCommitmentsAndContingenciesComponentsOfLeaseExpenseDetails" roleURI="http://www.bicycletherapeutics.com/role/DisclosureCommitmentsAndContingenciesComponentsOfLeaseExpenseDetails" />
  <link:roleRef xlink:type="simple" xlink:href="bcyc-20260331.xsd#DisclosureCommitmentsAndContingenciesLeasesMaturitiesOfOperatingLeasesDetails" roleURI="http://www.bicycletherapeutics.com/role/DisclosureCommitmentsAndContingenciesLeasesMaturitiesOfOperatingLeasesDetails" />
  <link:roleRef xlink:type="simple" xlink:href="bcyc-20260331.xsd#DisclosureSegmentsAndGeographicInformationSignificantSegmentExpensesDetails" roleURI="http://www.bicycletherapeutics.com/role/DisclosureSegmentsAndGeographicInformationSignificantSegmentExpensesDetails" />
  <link:arcroleRef arcroleURI="https://xbrl.org/2023/arcrole/summation-item" xlink:type="simple" xlink:href="https://www.xbrl.org/2023/calculation-1.1.xsd#summation-item" />
  <link:calculationLink xlink:role="http://www.bicycletherapeutics.com/role/StatementCondensedConsolidatedBalanceSheets" xlink:type="extended" xlink:title="995200100 - Statement - Condensed Consolidated Balance Sheets">
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_Assets" xlink:label="us-gaap_Assets" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AssetsCurrent" xlink:label="us-gaap_AssetsCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_Assets" xlink:to="us-gaap_AssetsCurrent_639130112833840101" order="1" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CashAndCashEquivalentsAtCarryingValue" xlink:label="us-gaap_CashAndCashEquivalentsAtCarryingValue_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_AssetsCurrent_639130112833840101" xlink:to="us-gaap_CashAndCashEquivalentsAtCarryingValue_639130112833840101" order="1" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PrepaidExpenseAndOtherAssetsCurrent" xlink:label="us-gaap_PrepaidExpenseAndOtherAssetsCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_AssetsCurrent_639130112833840101" xlink:to="us-gaap_PrepaidExpenseAndOtherAssetsCurrent_639130112833840101" order="2" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_ResearchAndDevelopmentIncentivesReceivableCurrent" xlink:label="bcyc_ResearchAndDevelopmentIncentivesReceivableCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_AssetsCurrent_639130112833840101" xlink:to="bcyc_ResearchAndDevelopmentIncentivesReceivableCurrent_639130112833840101" order="3" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PropertyPlantAndEquipmentNet" xlink:label="us-gaap_PropertyPlantAndEquipmentNet_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_Assets" xlink:to="us-gaap_PropertyPlantAndEquipmentNet_639130112833840101" order="2" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseRightOfUseAsset" xlink:label="us-gaap_OperatingLeaseRightOfUseAsset_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_Assets" xlink:to="us-gaap_OperatingLeaseRightOfUseAsset_639130112833840101" order="3" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherAssetsNoncurrent" xlink:label="us-gaap_OtherAssetsNoncurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_Assets" xlink:to="us-gaap_OtherAssetsNoncurrent_639130112833840101" order="4" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LiabilitiesAndStockholdersEquity" xlink:label="us-gaap_LiabilitiesAndStockholdersEquity" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_Liabilities" xlink:label="us-gaap_Liabilities_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesAndStockholdersEquity" xlink:to="us-gaap_Liabilities_639130112833840101" order="1" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LiabilitiesCurrent" xlink:label="us-gaap_LiabilitiesCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_Liabilities_639130112833840101" xlink:to="us-gaap_LiabilitiesCurrent_639130112833840101" order="1" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccountsPayableCurrent" xlink:label="us-gaap_AccountsPayableCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesCurrent_639130112833840101" xlink:to="us-gaap_AccountsPayableCurrent_639130112833840101" order="1" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccruedLiabilitiesCurrent" xlink:label="us-gaap_AccruedLiabilitiesCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesCurrent_639130112833840101" xlink:to="us-gaap_AccruedLiabilitiesCurrent_639130112833840101" order="2" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DeferredRevenueCurrent" xlink:label="us-gaap_DeferredRevenueCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesCurrent_639130112833840101" xlink:to="us-gaap_DeferredRevenueCurrent_639130112833840101" order="3" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DeferredRevenueNoncurrent" xlink:label="us-gaap_DeferredRevenueNoncurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_Liabilities_639130112833840101" xlink:to="us-gaap_DeferredRevenueNoncurrent_639130112833840101" order="2" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseLiabilityNoncurrent" xlink:label="us-gaap_OperatingLeaseLiabilityNoncurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_Liabilities_639130112833840101" xlink:to="us-gaap_OperatingLeaseLiabilityNoncurrent_639130112833840101" order="3" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherLiabilitiesNoncurrent" xlink:label="us-gaap_OtherLiabilitiesNoncurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_Liabilities_639130112833840101" xlink:to="us-gaap_OtherLiabilitiesNoncurrent_639130112833840101" order="4" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockholdersEquity" xlink:label="us-gaap_StockholdersEquity_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesAndStockholdersEquity" xlink:to="us-gaap_StockholdersEquity_639130112833840101" order="2" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockValue" xlink:label="us-gaap_CommonStockValue_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_StockholdersEquity_639130112833840101" xlink:to="us-gaap_CommonStockValue_639130112833840101" order="1" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AdditionalPaidInCapital" xlink:label="us-gaap_AdditionalPaidInCapital_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_StockholdersEquity_639130112833840101" xlink:to="us-gaap_AdditionalPaidInCapital_639130112833840101" order="2" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax" xlink:label="us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_StockholdersEquity_639130112833840101" xlink:to="us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax_639130112833840101" order="3" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RetainedEarningsAccumulatedDeficit" xlink:label="us-gaap_RetainedEarningsAccumulatedDeficit_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_StockholdersEquity_639130112833840101" xlink:to="us-gaap_RetainedEarningsAccumulatedDeficit_639130112833840101" order="4" use="optional" weight="1" priority="1" />
  </link:calculationLink>
  <link:calculationLink xlink:role="http://www.bicycletherapeutics.com/role/StatementCondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss" xlink:type="extended" xlink:title="995200200 - Statement - Condensed Consolidated Statements of Operations and Comprehensive Loss">
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ComprehensiveIncomeNetOfTax" xlink:label="us-gaap_ComprehensiveIncomeNetOfTax" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetIncomeLoss" xlink:label="us-gaap_NetIncomeLoss_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_ComprehensiveIncomeNetOfTax" xlink:to="us-gaap_NetIncomeLoss_639130112833840101" order="1" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:label="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetIncomeLoss_639130112833840101" xlink:to="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_639130112833840101" order="1" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingIncomeLoss" xlink:label="us-gaap_OperatingIncomeLoss_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_639130112833840101" xlink:to="us-gaap_OperatingIncomeLoss_639130112833840101" order="1" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax" xlink:label="us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_OperatingIncomeLoss_639130112833840101" xlink:to="us-gaap_RevenueFromContractWithCustomerExcludingAssessedTax_639130112833840101" order="1" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingExpenses" xlink:label="us-gaap_OperatingExpenses_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_OperatingIncomeLoss_639130112833840101" xlink:to="us-gaap_OperatingExpenses_639130112833840101" order="2" use="optional" weight="-1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ResearchAndDevelopmentExpense" xlink:label="us-gaap_ResearchAndDevelopmentExpense_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_OperatingExpenses_639130112833840101" xlink:to="us-gaap_ResearchAndDevelopmentExpense_639130112833840101" order="1" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_GeneralAndAdministrativeExpense" xlink:label="us-gaap_GeneralAndAdministrativeExpense_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_OperatingExpenses_639130112833840101" xlink:to="us-gaap_GeneralAndAdministrativeExpense_639130112833840101" order="2" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NonoperatingIncomeExpense" xlink:label="us-gaap_NonoperatingIncomeExpense_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_639130112833840101" xlink:to="us-gaap_NonoperatingIncomeExpense_639130112833840101" order="2" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_InterestAndOtherIncome" xlink:label="us-gaap_InterestAndOtherIncome_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NonoperatingIncomeExpense_639130112833840101" xlink:to="us-gaap_InterestAndOtherIncome_639130112833840101" order="1" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_InterestExpenseNonoperating" xlink:label="us-gaap_InterestExpenseNonoperating_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NonoperatingIncomeExpense_639130112833840101" xlink:to="us-gaap_InterestExpenseNonoperating_639130112833840101" order="2" use="optional" weight="-1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeTaxExpenseBenefit" xlink:label="us-gaap_IncomeTaxExpenseBenefit_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetIncomeLoss_639130112833840101" xlink:to="us-gaap_IncomeTaxExpenseBenefit_639130112833840101" order="2" use="optional" weight="-1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationAdjustmentNetOfTaxPortionAttributableToParent" xlink:label="us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationAdjustmentNetOfTaxPortionAttributableToParent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_ComprehensiveIncomeNetOfTax" xlink:to="us-gaap_OtherComprehensiveIncomeForeignCurrencyTransactionAndTranslationAdjustmentNetOfTaxPortionAttributableToParent_639130112833840101" order="2" use="optional" weight="1" priority="2" />
  </link:calculationLink>
  <link:calculationLink xlink:role="http://www.bicycletherapeutics.com/role/StatementCondensedConsolidatedStatementsOfCashFlows" xlink:type="extended" xlink:title="995200400 - Statement - Condensed Consolidated Statements of Cash Flows">
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" xlink:label="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CashAndCashEquivalentsAtCarryingValue" xlink:label="us-gaap_CashAndCashEquivalentsAtCarryingValue_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" xlink:to="us-gaap_CashAndCashEquivalentsAtCarryingValue_639130112833840101" order="1" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RestrictedCashAndCashEquivalentsNoncurrent" xlink:label="us-gaap_RestrictedCashAndCashEquivalentsNoncurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" xlink:to="us-gaap_RestrictedCashAndCashEquivalentsNoncurrent_639130112833840101" order="2" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RestrictedCashEquivalentsCurrent" xlink:label="us-gaap_RestrictedCashEquivalentsCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" xlink:to="us-gaap_RestrictedCashEquivalentsCurrent_639130112833840101" order="3" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:label="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" order="1" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ProfitLoss" xlink:label="us-gaap_ProfitLoss_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="us-gaap_ProfitLoss_639130112833840101" order="1" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ShareBasedCompensation" xlink:label="us-gaap_ShareBasedCompensation_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="us-gaap_ShareBasedCompensation_639130112833840101" order="2" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DepreciationDepletionAndAmortization" xlink:label="us-gaap_DepreciationDepletionAndAmortization_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="us-gaap_DepreciationDepletionAndAmortization_639130112833840101" order="3" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DeferredIncomeTaxExpenseBenefit" xlink:label="us-gaap_DeferredIncomeTaxExpenseBenefit_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="us-gaap_DeferredIncomeTaxExpenseBenefit_639130112833840101" order="4" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInOperatingLeaseLiability" xlink:label="us-gaap_IncreaseDecreaseInOperatingLeaseLiability_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="us-gaap_IncreaseDecreaseInOperatingLeaseLiability_639130112833840101" order="5" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInAccountsReceivable" xlink:label="us-gaap_IncreaseDecreaseInAccountsReceivable_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="us-gaap_IncreaseDecreaseInAccountsReceivable_639130112833840101" order="6" use="optional" weight="-1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_IncreaseDecreaseInResearchAndDevelopmentIncentivesReceivable" xlink:label="bcyc_IncreaseDecreaseInResearchAndDevelopmentIncentivesReceivable_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="bcyc_IncreaseDecreaseInResearchAndDevelopmentIncentivesReceivable_639130112833840101" order="7" use="optional" weight="-1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets" xlink:label="us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets_639130112833840101" order="8" use="optional" weight="-1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_IncreaseDecreaseInOperatingLeaseRightOfUseAssets" xlink:label="bcyc_IncreaseDecreaseInOperatingLeaseRightOfUseAssets_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="bcyc_IncreaseDecreaseInOperatingLeaseRightOfUseAssets_639130112833840101" order="9" use="optional" weight="-1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInAccountsPayable" xlink:label="us-gaap_IncreaseDecreaseInAccountsPayable_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="us-gaap_IncreaseDecreaseInAccountsPayable_639130112833840101" order="10" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities" xlink:label="us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities_639130112833840101" order="11" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInDeferredRevenue" xlink:label="us-gaap_IncreaseDecreaseInDeferredRevenue_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities_639130112833840101" xlink:to="us-gaap_IncreaseDecreaseInDeferredRevenue_639130112833840101" order="12" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivities_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:to="us-gaap_NetCashProvidedByUsedInInvestingActivities_639130112833840101" order="2" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" xlink:label="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivities_639130112833840101" xlink:to="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment_639130112833840101" order="1" use="optional" weight="-1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivities_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivities_639130112833840101" order="3" use="optional" weight="1" priority="2" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ProceedsFromStockOptionsExercised" xlink:label="us-gaap_ProceedsFromStockOptionsExercised_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivities_639130112833840101" xlink:to="us-gaap_ProceedsFromStockOptionsExercised_639130112833840101" order="1" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FinanceLeasePrincipalPayments" xlink:label="us-gaap_FinanceLeasePrincipalPayments_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivities_639130112833840101" xlink:to="us-gaap_FinanceLeasePrincipalPayments_639130112833840101" order="2" use="optional" weight="-1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EffectOfExchangeRateOnCashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsIncludingDisposalGroupAndDiscontinuedOperations" xlink:label="us-gaap_EffectOfExchangeRateOnCashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsIncludingDisposalGroupAndDiscontinuedOperations_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:to="us-gaap_EffectOfExchangeRateOnCashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsIncludingDisposalGroupAndDiscontinuedOperations_639130112833840101" order="4" use="optional" weight="1" priority="2" />
  </link:calculationLink>
  <link:calculationLink xlink:role="http://www.bicycletherapeutics.com/role/DisclosurePropertyAndEquipmentNetDetails" xlink:type="extended" xlink:title="99940401 - Disclosure - Property and equipment, net (Details)">
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PropertyPlantAndEquipmentAndFinanceLeaseRightOfUseAssetAfterAccumulatedDepreciationAndAmortization" xlink:label="us-gaap_PropertyPlantAndEquipmentAndFinanceLeaseRightOfUseAssetAfterAccumulatedDepreciationAndAmortization" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PropertyPlantAndEquipmentAndFinanceLeaseRightOfUseAssetAccumulatedDepreciationAndAmortization" xlink:label="us-gaap_PropertyPlantAndEquipmentAndFinanceLeaseRightOfUseAssetAccumulatedDepreciationAndAmortization_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_PropertyPlantAndEquipmentAndFinanceLeaseRightOfUseAssetAfterAccumulatedDepreciationAndAmortization" xlink:to="us-gaap_PropertyPlantAndEquipmentAndFinanceLeaseRightOfUseAssetAccumulatedDepreciationAndAmortization_639130112833840101" order="1" use="optional" weight="-1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PropertyPlantAndEquipmentAndFinanceLeaseRightOfUseAssetBeforeAccumulatedDepreciationAndAmortization" xlink:label="us-gaap_PropertyPlantAndEquipmentAndFinanceLeaseRightOfUseAssetBeforeAccumulatedDepreciationAndAmortization_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_PropertyPlantAndEquipmentAndFinanceLeaseRightOfUseAssetAfterAccumulatedDepreciationAndAmortization" xlink:to="us-gaap_PropertyPlantAndEquipmentAndFinanceLeaseRightOfUseAssetBeforeAccumulatedDepreciationAndAmortization_639130112833840101" order="2" use="optional" weight="1" />
  </link:calculationLink>
  <link:calculationLink xlink:role="http://www.bicycletherapeutics.com/role/DisclosureAccruedExpensesAndOtherCurrentLiabilitiesDetails" xlink:type="extended" xlink:title="99940501 - Disclosure - Accrued expenses and other current liabilities (Details)">
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccruedLiabilitiesCurrent" xlink:label="us-gaap_AccruedLiabilitiesCurrent" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_EmployeeRelatedLiabilitiesCurrent" xlink:label="us-gaap_EmployeeRelatedLiabilitiesCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_AccruedLiabilitiesCurrent" xlink:to="us-gaap_EmployeeRelatedLiabilitiesCurrent_639130112833840101" order="1" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_AccruedExternalResearchAndDevelopmentExpenses" xlink:label="bcyc_AccruedExternalResearchAndDevelopmentExpenses_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_AccruedLiabilitiesCurrent" xlink:to="bcyc_AccruedExternalResearchAndDevelopmentExpenses_639130112833840101" order="2" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccruedProfessionalFeesCurrent" xlink:label="us-gaap_AccruedProfessionalFeesCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_AccruedLiabilitiesCurrent" xlink:to="us-gaap_AccruedProfessionalFeesCurrent_639130112833840101" order="3" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseLiabilityCurrent" xlink:label="us-gaap_OperatingLeaseLiabilityCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_AccruedLiabilitiesCurrent" xlink:to="us-gaap_OperatingLeaseLiabilityCurrent_639130112833840101" order="4" use="optional" weight="1" priority="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FinanceLeaseLiabilityCurrent" xlink:label="us-gaap_FinanceLeaseLiabilityCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_AccruedLiabilitiesCurrent" xlink:to="us-gaap_FinanceLeaseLiabilityCurrent_639130112833840101" order="5" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherLiabilitiesCurrent" xlink:label="us-gaap_OtherLiabilitiesCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_AccruedLiabilitiesCurrent" xlink:to="us-gaap_OtherLiabilitiesCurrent_639130112833840101" order="6" use="optional" weight="1" priority="1" />
  </link:calculationLink>
  <link:calculationLink xlink:role="http://www.bicycletherapeutics.com/role/DisclosureSignificantAgreementsRevenueRecognitionDueToChangesInContractAssetsAndLiabilitiesDetails" xlink:type="extended" xlink:title="99940808 - Disclosure - Significant agreements - Revenue recognition due to changes in contract assets and liabilities (Details)">
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_TotalRevenueRecognizedFromBothBeginningBalanceAndCurrentPeriodIncreaseInContractLiability" xlink:label="bcyc_TotalRevenueRecognizedFromBothBeginningBalanceAndCurrentPeriodIncreaseInContractLiability" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_ContractWithCustomerLiabilityRevenueRecognizedProportionalPerformanceObligation" xlink:label="bcyc_ContractWithCustomerLiabilityRevenueRecognizedProportionalPerformanceObligation_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="bcyc_TotalRevenueRecognizedFromBothBeginningBalanceAndCurrentPeriodIncreaseInContractLiability" xlink:to="bcyc_ContractWithCustomerLiabilityRevenueRecognizedProportionalPerformanceObligation_639130112833840101" order="1" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_ContractWithCustomerLiabilityRevenueRecognizedContractModificationsAndExpirationOfMaterialRights" xlink:label="bcyc_ContractWithCustomerLiabilityRevenueRecognizedContractModificationsAndExpirationOfMaterialRights_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="bcyc_TotalRevenueRecognizedFromBothBeginningBalanceAndCurrentPeriodIncreaseInContractLiability" xlink:to="bcyc_ContractWithCustomerLiabilityRevenueRecognizedContractModificationsAndExpirationOfMaterialRights_639130112833840101" order="2" use="optional" weight="1" />
  </link:calculationLink>
  <link:calculationLink xlink:role="http://www.bicycletherapeutics.com/role/DisclosureCommitmentsAndContingenciesComponentsOfLeaseExpenseDetails" xlink:type="extended" xlink:title="99941002 - Disclosure - Commitments and contingencies - Components of lease expense (Details)">
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_FinanceLeaseCost" xlink:label="bcyc_FinanceLeaseCost" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FinanceLeaseRightOfUseAssetAmortization" xlink:label="us-gaap_FinanceLeaseRightOfUseAssetAmortization_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="bcyc_FinanceLeaseCost" xlink:to="us-gaap_FinanceLeaseRightOfUseAssetAmortization_639130112833840101" order="1" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FinanceLeaseInterestExpense" xlink:label="us-gaap_FinanceLeaseInterestExpense_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="bcyc_FinanceLeaseCost" xlink:to="us-gaap_FinanceLeaseInterestExpense_639130112833840101" order="2" use="optional" weight="1" />
  </link:calculationLink>
  <link:calculationLink xlink:role="http://www.bicycletherapeutics.com/role/DisclosureCommitmentsAndContingenciesLeasesMaturitiesOfOperatingLeasesDetails" xlink:type="extended" xlink:title="99941003 - Disclosure - Commitments and contingencies - Leases, Maturities of Operating Leases (Details)">
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FinanceLeaseLiability" xlink:label="us-gaap_FinanceLeaseLiability_1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FinanceLeaseLiabilityCurrent" xlink:label="us-gaap_FinanceLeaseLiabilityCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_FinanceLeaseLiability_1" xlink:to="us-gaap_FinanceLeaseLiabilityCurrent_639130112833840101" order="1" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FinanceLeaseLiabilityNoncurrent" xlink:label="us-gaap_FinanceLeaseLiabilityNoncurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_FinanceLeaseLiability_1" xlink:to="us-gaap_FinanceLeaseLiabilityNoncurrent_639130112833840101" order="2" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseLiability" xlink:label="us-gaap_OperatingLeaseLiability" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseLiabilityCurrent" xlink:label="us-gaap_OperatingLeaseLiabilityCurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_OperatingLeaseLiability" xlink:to="us-gaap_OperatingLeaseLiabilityCurrent_639130112833840101" order="1" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseLiabilityNoncurrent" xlink:label="us-gaap_OperatingLeaseLiabilityNoncurrent_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_OperatingLeaseLiability" xlink:to="us-gaap_OperatingLeaseLiabilityNoncurrent_639130112833840101" order="2" use="optional" weight="1" />
  </link:calculationLink>
  <link:calculationLink xlink:role="http://www.bicycletherapeutics.com/role/DisclosureSegmentsAndGeographicInformationSignificantSegmentExpensesDetails" xlink:type="extended" xlink:title="99941202 - Disclosure - Segments and geographic information - Significant segment expenses (Details)">
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_GeneralAndAdministrativeExpense" xlink:label="us-gaap_GeneralAndAdministrativeExpense" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ForeignCurrencyTransactionGainLossBeforeTax" xlink:label="us-gaap_ForeignCurrencyTransactionGainLossBeforeTax_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_GeneralAndAdministrativeExpense" xlink:to="us-gaap_ForeignCurrencyTransactionGainLossBeforeTax_639130112833840101" order="1" use="optional" weight="-1" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_GeneralAndAdministrativeShareBasedPaymentArrangementExpense" xlink:label="bcyc_GeneralAndAdministrativeShareBasedPaymentArrangementExpense_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_GeneralAndAdministrativeExpense" xlink:to="bcyc_GeneralAndAdministrativeShareBasedPaymentArrangementExpense_639130112833840101" order="2" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherGeneralAndAdministrativeExpense" xlink:label="us-gaap_OtherGeneralAndAdministrativeExpense_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_GeneralAndAdministrativeExpense" xlink:to="us-gaap_OtherGeneralAndAdministrativeExpense_639130112833840101" order="3" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ProfessionalFees" xlink:label="us-gaap_ProfessionalFees_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_GeneralAndAdministrativeExpense" xlink:to="us-gaap_ProfessionalFees_639130112833840101" order="4" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LaborAndRelatedExpense" xlink:label="us-gaap_LaborAndRelatedExpense_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_GeneralAndAdministrativeExpense" xlink:to="us-gaap_LaborAndRelatedExpense_639130112833840101" order="5" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ResearchAndDevelopmentExpense" xlink:label="us-gaap_ResearchAndDevelopmentExpense" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_ResearchAndDevelopmentTaxCreditsIncentivesAndGovernmentGrants" xlink:label="bcyc_ResearchAndDevelopmentTaxCreditsIncentivesAndGovernmentGrants_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_ResearchAndDevelopmentExpense" xlink:to="bcyc_ResearchAndDevelopmentTaxCreditsIncentivesAndGovernmentGrants_639130112833840101" order="1" use="optional" weight="-1" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_FacilityExpenses" xlink:label="bcyc_FacilityExpenses_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_ResearchAndDevelopmentExpense" xlink:to="bcyc_FacilityExpenses_639130112833840101" order="2" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_ResearchAndDevelopmentShareBasedPaymentArrangementExpense" xlink:label="bcyc_ResearchAndDevelopmentShareBasedPaymentArrangementExpense_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_ResearchAndDevelopmentExpense" xlink:to="bcyc_ResearchAndDevelopmentShareBasedPaymentArrangementExpense_639130112833840101" order="3" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_ResearchAndDevelopmentEmployeeAndContractorRelatedExpenses" xlink:label="bcyc_ResearchAndDevelopmentEmployeeAndContractorRelatedExpenses_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_ResearchAndDevelopmentExpense" xlink:to="bcyc_ResearchAndDevelopmentEmployeeAndContractorRelatedExpenses_639130112833840101" order="4" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_ResearchAndDevelopmentDiscoveryPlatformAndOtherExpenses" xlink:label="bcyc_ResearchAndDevelopmentDiscoveryPlatformAndOtherExpenses_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_ResearchAndDevelopmentExpense" xlink:to="bcyc_ResearchAndDevelopmentDiscoveryPlatformAndOtherExpenses_639130112833840101" order="5" use="optional" weight="1" />
    <link:loc xlink:type="locator" xlink:href="bcyc-20260331.xsd#bcyc_ProjectSpecificCosts" xlink:label="bcyc_ProjectSpecificCosts_639130112833840101" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="us-gaap_ResearchAndDevelopmentExpense" xlink:to="bcyc_ProjectSpecificCosts_639130112833840101" order="6" use="optional" weight="1" />
  </link:calculationLink>
</link:linkbase>
